The Role of ABC Transporters in Ovarian Cancer Progression and Chemoresistance

Critical Reviews in Oncology/Hematology 96 (2015) 220256
The role of ABC transporters in ovarian cancer progression and

chemoresistance
M.P. Ween a , M.A. Armstrong b , M.K. Oehler c,d , C. Ricciardelli d,
a
Lung Research, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide
b Data Management and Analysis Centre, University of Adelaide, Australia
c Gynaecological Oncology Department, Royal Adelaide Hospital, Australia
School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Australia
Accepted 18 May 2015
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
2.1. The ABCA family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
2.1.1. ABCA1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
2.1.2. ABCA2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
2.1.3. ABCA3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
2.1.4. ABCA4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
2.1.5. ABCA5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
2.1.6. ABCA6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.1.7. ABCA7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.1.8. ABCA8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.1.9. ABCA9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.1.10. ABCA10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.1.11. ABCA12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.2. The ABCB family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.2.1. ABCB1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
2.2.2. ABCB2 and ABCB3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
2.2.3. ABCB4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
2.2.4. ABCB5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
2.2.5. ABCB6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
2.2.6. ABCB7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
2.2.7. ABCB8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
2.2.8. ABCB9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
2.2.9. ABCB10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
2.2.10. ABCB11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
2.3. The ABCC family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
2.3.1. ABCC1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
2.3.2. ABCC2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2.3.3. ABCC3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2.3.4. ABCC4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
2.3.5. ABCC5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Corresponding author at: The University of Adelaide, School of Paediatrics and Reproductive Health, Medical School North, University of Adelaide, Frome
Rd., Adelaide 5005, Australia. Tel.: +61 08 8313 8255; fax: +61 08 8313 6387.
E-mail address: carmela.ricciardelli@adelaide.edu.au (C. Ricciardelli).
http://dx.doi.org/10.1016/j.critrevonc.2015.05.012
1040-8428/ 2015 Elsevier Ireland Ltd. All rights reserved.
M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256
3.
4.
5.
6.
221
2.3.6. ABCC6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

2.3.7. ABCC7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
2.3.8. ABCC8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.3.9. ABCC9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.3.10. ABCC10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.3.11. ABCC11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.3.12. ABCC12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.4. The ABCD family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.4.1. ABCD1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.4.2. ABCD2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.4.3. ABCD3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2.4.4. ABCD4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.5. The ABCE family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.5.1. ABCE1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.6. The ABCF family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.6.1. ABCF1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.6.2. ABCF2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.6.3. ABCF3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.7. The ABCG family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.7.1. ABCG1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.7.2. ABCG2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.7.3. ABCG4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
2.7.4. ABCG5 and ABCG8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Cancer stem cells and ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Clinical trials using inhibitors of ABC transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Alternative strategies to overcome ovarian cancer MDR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Abstract
Over 80% of ovarian cancer patients develop chemoresistance which results in a lethal course of the disease. A well-established cause
of chemoresistance involves the family of ATP-binding cassette transporters, or ABC transporters that transport a wide range of substrates
including metabolic products, nutrients, lipids, and drugs across extra- and intra-cellular membranes. Expressions of various ABC transporters,
shown to reduce the intracellular accumulation of chemotherapy drugs, are increased following chemotherapy and impact on ovarian cancer
survival. Although clinical trials to date using ABC transporter inhibitors have been disappointing, ABC transporter inhibition remains an
attractive potential adjuvant to chemotherapy. A greater understanding of their physiological functions and role in ovarian cancer chemoresistance will be important for the development of more effective targeted therapies. This article will review the role of the ABC transporter
family in ovarian cancer progression and chemoresistance as well as the clinical attempts used to date to reverse chemoresistance.
2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Ovarian cancer; ABC transporter; Chemoresistance; Multi-drug resistance; Prognosis; Clinical trials
1. Introduction
Ovarian cancer is the most lethal gynaecological cancer
and ranks as the sixth most common cause of cancer-related
death in women in the Western world [1]. Unfortunately,
ovarian cancer often goes undetected due to vague symptoms and is rarely diagnosed at an early stage which has
a substantially higher survival rate than advanced disease
[24]. Despite a high initial response to chemotherapy, the
majority of patients with advanced ovarian cancer relapse and
subsequently develop chemoresistance which results in treatment failure and death of the patient [5]. Chemoresistance,
either intrinsic or acquired, is the main factor contributing to ovarian cancer death. Cancer cells often develop
resistance to many functionally and structurally unrelated
anti-cancer drugs, including those not yet given to patients,
a phenomenon known as multidrug resistance (MDR). It is
believed that chemoresistance develops for two main reasons. Tumours may be populated by a minority of resistance
cells including tumour cells with stem cell like properties
222
that have inherent resistance to drugs and are capable of

repopulating the tumour after treatment [6]. Alternatively,
tumour cells acquire resistance as a result of chemotherapy treatment induced changes. Multiple mechanisms have
been characterized which include changes in cellular repair
mechanisms, alterations in apoptotic pathways, increased
or decreased expression of metabolic enzymes, mutations,
alterations in the tumour microenvironment and increased
expression/activity of drug efflux pumps and altered uptake
pathways which result in reduced cellular accumulation of
chemotherapy drugs [79]. One of the most important MDR
mechanisms is an increased efflux rate of anti-cancer drugs
from cancer cells by members of the ATP-binding cassette
(ABC) transporters family [10]. This review will discuss the
role of the ABC transporter family in ovarian cancer progression and chemoresistance.
2. ABC transporters
ABC transporters transport a wide range of substrates,
including metabolic products, nutrients, lipids, and drugs,
across extracellular and intracellular membranes, and have
been shown to play an important role in many human diseases
[1122]. ABC transporters differ from classical selective
transporters by way of their promiscuity for structurally
and chemically diverse substrates [23]. Phylogenetic analysis
places the 48 known human ABC transporters into 7 distinct
subfamilies (ABCA-ABCG, Table 1) [24]. ABC transporters
are complex translocation systems that couple the hydrolysis
of ATP to the unidirectional movement of a wide range of distinct compounds across the phospholipid bilayer of cellular
membranes. All ABC transporters consist of transmembrane
domains (TMDs) and nucleotide-binding domains (NBDs).
In humans, they either contain one, two, or three TMDs paired
with an NBD (Fig. 1) The NBDs act as motor domains
by hydrolysing ATP molecules to drive the transport cycle
(Fig. 2) [2527]. Whilst ABC transporters have many physiological functions, they are best known for their involvement
in drug efflux. In fact, a single ABC transporter can be capable
of transporting a wide range of structurally and chemically
diverse substrates, both physiological as well as chemotherapeutic. A thorough review of the literature has found that
currently, at least 20 ABC transporters are capable of exporting anti-cancer drugs (Table 1). It is even thought that ABC
transporters may be capable of transporting multiple substrates at once [28]. However, it remains unclear why ABC
transporters have such a vast range of substrates, but it is
believed that they contain many different substrate recognition sites. A greater understanding this phenomenon will
allow for a greater ability to inhibit the chemotherapeutic
efflux capacity of ABC transporters [29].
Only a handful of ABC transporter crystal structures
are currently available. After the retraction of the incorrect
structures of MsbA [30] there was only one high resolution structure of an ABC exporter, Staphylococcus aureus
Sav1866 protein available [31,32]. However, recent publications have elucidated TM287-TM288 (TM287/288) from
Thermotoga maritima [33], mouse ABCB1 [34], Pyrococcus abyssi ABCE1 [35,36], Caenorhabditis elegans ABCB1
[37], and also human ABCB10 [38] (Fig. 3). A very recent
paper shows ABCB1 interacting with several designed ligands and provides useful insight in understanding how ABC
transporters can recognise a wide range of structurally diverse
ligands [39].
2.1. The ABCA family
2.1.1. ABCA1
ABCA1 mediates the apolipoprotein-dependent formation of a high-density lipoproteincholesterol complex [40].
Very little is known about its role in cancer, but a recent
study found ABCA1 was elevated in radiation surviving
medulloblastoma cells and broad ABC exporter inhibitors
verapamil and reserpine could resensitise cells to radiotherapy [41]. ABCA1 was also found to be up-regulated in
pancreatic ductal adenocarcinomas [42] and was part of a
gene signature predicting higher risk of relapse in colon
cancer patients [43]. Increased ABCA1 expression was also
shown to be associated with poor treatment response in breast
cancer patients [44]. Two recent studies suggest it also plays
a role in ovarian cancer. The first showed that ABCA1 was
significantly associated with reduced overall survival (OS)
in serous ovarian cancer patients in two independent datasets
and the suppression of ABCA1 expression lead to reduced
ovarian cancer cell growth and migration [45]. The second
found higher ABCA1 methylation levels in ovarian cancer
tissues compared to normal ovaries and was associated with
significantly shorter progression-free survival (PFS) [46].
Lentiviral knockdown of ABCA1 in cisplatin resistant ovarian cancer cells resulted in their re-sensitisation, representing
the first evidence that ABCA1 may play a role in drug resistance [47]. These findings are supported by Oiso et al. that
found ABCA1 was up-regulated in cisplatin resistant human
epidermoid carcinoma cells compared to the parental cells
[48].
2.1.2. ABCA2
ABCA2 has been suggested to be involved in intracellular
sterol regulation [49]. ABCB2 expression has been reported
to be up-regulated in melanoma [50], hepatocellular carcinoma [51], breast cancer [52], colon adenocarcinoma [53]
and leukaemia [54,55]. A single study in ovarian cancer found
up-regulated ABCA2 expression in an estramustine resistant
strain of SKOV-3 compared with the parent cell line [56].
Antisense targeting of ABCA2 resulted in downregulation of
ABCA2 and re-sensitisation to estramustine [56]. Increased
survival in the presence of cytotoxic agents is thought to be
due to the capacity of ABCA2 to sequester drugs into lysosomal organelles. Human Protein Atlas (HPA) shows medium
or high ABCA2 expression in ovarian tumour cells in all 12 of
223
Table 1
Human ABC transporters and their known substrates and inhibitors.
Names
Cancer drug substrates
Inhibitors
ABCA1
ABC1
HDLDT1
TGD
CERP
ABCA2
ABC2
KIAA1062
ABCA3
ABC3
ABCC
Cisplatin [47]
Glibenclamide/Glyburide [383], JNJ-26854165 [384]
Mitoxantrone [385], Estramustine [385], Methotrexate [54]
None identified
ABCA4
ABCR
ABCA5
ABCA6
EST155051
ABCA7
ABCX
ABCA-SSN
ABCA8
KIAA082
ABCA9
EST640918
ABCA10
EST698739
ABCA12
ABCA13
ABCB1
MDR1
Pgp
GP170
PGY1
MDR/TAP ABC20
CD243
ABCB2
TAP1
ABCB3
TAP2
ABCB4
PGP3
MDR3
PGY3
MDR3 PGP1111
GBD1
PFIC-3
ABC21
ABCB5
ABCB6
MTABC3
ABCB7
ABC7
Cisplatin [59], Dasatinib [386], Daunorubicin [387], Doxorubicin Genistein [388], Indomethacin [386], PK11195 [389]
[55], Etoposide [387], Imatinib [386], Methotrexate [54],
Mitoxantrone [387], Nilotinib [386], Paclitaxel [59], Vincristine
[387]
None identified
None identified
None identified
None identified
U0126 [390]
IGF-1 [391]
None identified
None identified
Digoxin [392]
None identified
MS-209 [393], MK-571[393]1, Ochratoxin A [393],

Verapamil [393], Probenecid [393]
None identified
None identified
None identified
None identified
None identified
5-Fluorouracil [394], Actinomycin D [395], Bisantrene [396],
Dasatinib [397], Daunorubicin [78], Digoxin [398], Docetaxel
[399], Doxorubicin [400], Epirubicin [401], Etoposide/VP-16
[402], Homoharringtonine [403], Irinotecan [404], Mitoxantrone
[317], Paclitaxel [405], Teniposide [406], Topotecan [407],
Vinblastine [408], Vincristine [408], Vindesine [408], Vinorelbine
[408]
None identified
None identified
None identified
Agosterol A [409], Annamycin [410], Anthranilamide
[411], Antimalarials [412,413], Apatinib [414], BBA [415],
CBT-1 [416], Curcumin [353], Cyclosporin A [417],
Disulfiram [418], Dofequidar [419],
Elacridar/GG918/GF120918 [420], Epigallocatechin
gallates [348], FG020326 [421], Flavinoids [422],
Ginsenosides [423], HG-829 [424], Ko143 [425], Lapatinib
[426], Latilagascenes [427], Mitotane/NSC-38721 [428],
MK571 [425], Monoterpenoids [429], MS-209 [430],
Neratinib [431], OC-144-093/ONT-093 [432], Piperine
[433], PK11195 [434], Pluronic L61 [420], Polyphenols
[348], Quinoline [435], R101933 [436], Reversan [320],
S9788 [437], Saracatinib [330], Tariquidar/XR-9576 [308],
U0126 [390], V-104 [420], Valspodar/PSC 833 [438],
Verapamil [439], VX-710/Biricodar [440], WK-x-34 [441],
Zosquidar/LY-335979 [442]
None identified
None identified
None identified
Daunorubicin [443], Digoxin [443], Paclitaxel [443], Vinblastine

[443]
Cyclosporin A [443], Valspodar/PSC833 [443], Verapamil

[443]
5-Fluorouracil [394], Camptothecin [394], Doxorubicin [286],

Irinotecan [394], Mitozantrone [394], Topotecan [394]
None identified
None identified
None identified
None Identified
None identified
224
Table 1 (Continued)
Names
Inhibitors
ABCB8
MABC1
ABCB9
ABCB10
MTABC2
ABCB11
SPGP
BSEP
ABCC1
MRP-1
CFTR/MRP
GS-X
ABC29
Doxorubicin [165]
None identified
None identified
None identified
None identified
None identified
Paclitaxel [175]
Cyclosporin A [175], Valspodar/PSC833 [175], Verapamil

[175]
ABCC2
MRP-2
cMOAT
ABCC3
MRP-3
cMOAT-2
ABCC4
MRP-4
MOAT-B
ABCC5
MRP-5
MOAT-C
ABCC6
MRP-6
ABCC7
CFTR
ABCC8
SUR1
ABCC9
SUR2
ABCC10
MRP-7
ABCC11
MRP-8
ABCC12
MRP-9
ABCD1
ALD
ABCD2
ALD1
ALDR
ABCD3
PXMP1
PMP70
ABCD4
PMP69
P70R
Chlorambucil [444], Daunorubicin [445], Doxorubicin [445],

Epirubicin [446], Etoposide/VP-16 [447], Glucuronide [448],
Imatinib [447], Irinotecan [447], Melphalan [444], Methotrexate
[447], Mitoxantrone [447], Paclitaxel [182], saquinivir [447],
SN-38 [447], Vinblastine [449], Vincristine [408], Vinorelbine
[450]
Agosterol A [409], Annamycin [451], Antimalarials [452],

Biricodar/VX-710 [453], CBT-1 [416], Clotrimazole [454],
Curcumin [353], Cyclosporin A [453], Disulfiram [418],
Dofequidar [419], Elacridar/GG918/GF120918 [453],
Flavinoids [422], Flavopiridol [455], Glibenclamide [456],
Glutathione ethacrynic acid [23], Indomethacin [457],
LY465803 [458], LY475776 [459], MK571 [460], MS-209
[453], Non-nucleoside RT inhibitors [460], Nucleoside RT
inhibitors [460], Piperine [433], PK11195 [434],
Polyphenols [349], Pyrrolopyrimidines [461], Reversan
[320], Sulindac [327], Tariquidar/XR-9576, V-104 [420],
Verapamil [453], VX-710/Biricodar [453]
Cyclosporin A [467], MK571 [467], Non-nucleoside RT
Carboplatin [462], Cisplatin [176], Doxorubicin [225],
Epirubicin [463], Etoposide/VP-16 [225], Irinotecan [464],
inhibitors [460], Nucleoside RT inhibitors [460], PAK-104P
Irinotecan/CPT-11 [225], Methotreaxate [448], Mitoxantrone [465], [467], Triptanthin [468], Valspodar/PSC833 [467]
Paclitaxel [225], saquinivir [463], SN-38 [225], Sulfinpyrazone
[466], Topotecan [463], Vinblastine [192], Vincristine [225]
Etoposide/VP-16 [469], Methotrexate [448], Tenoposide [469],
MK571 [460], Non-nucleoside RT inhibitors [460],
Vincristine [394]
Nucleoside RT inhibitors [460], U0126 [390]
5-Fluorouracil [470], 6-mercaptopurine [471], 6-thioguanine [471],
Bisantrene [394], Irinotecan/CPT11 [225], Methotrexate [471],
Nucleoside monophosphates [472], Topotecan [225], Vinblastine
[443]
5-Fluorouracil [471], 6-mercaptopurine [471], 6-thioguanine [471],
Bisantrene [394], Doxorubicin [286], Gemcitabine [471],
Methotrexate [474], Mitozantrone [394], Nucleoside
monophosphates
Cisplatin [475], Daunorubicin [475], Doxorubicin [475],
Etoposide/VP-16 [475], Tenopiside [475]
None identified
Antimalarials [452], MK571 [471], PCS833 [471],

Polyphenols [349], Sildenafil [473], Trequinsin [473],
Zaprinast [473]
None identified
None identified
None identified
None identified
MK571 [471], Polyphenols [349], Sildenafil [473],

Trequinsin [473], Zaprinas [473]
None identified
None identified
Docetaxel [225], Doxorubicin [225], Paclitaxel [225], Vinblastine Cyclosporin A [225], Erlotinib [477], Glycolithocholate-3[225], Vincristine [225], Vinorelbine [476]
sulfate [225], Imatinib [478], Lapatinib [477], LTC4 [225],
MK571 [225], Nilotonib [478], Sulfinpyrazone [476],
Tandutinib/MLN518 [479], Tariquidar/XR-9576 [480]
5-Fluorouracil [225], 6-mercaptopurine [481], ddC [225],
None identified
Methotrexate [225], Pemetrexed [482], PMEA [225]
None identified
None identified
None identified
None identified
None identified
None identified
None identified
None identified
None identified
None identified
None identified
None identified
225
Table 1 (Continued)
Names
Inhibitors
ABCE1
OABP
RNS41
ABCF1
ABC50
ABCF2
ABCF3
ABCG1
ABC8
White
ABCG2
BCRP
MXR1
ABCP
CD338
EST157481
ABC15
BMDP
MRX
ABCG4
White2
ABCG5
White3
STSL
Sterolin-1
ABCG8
GBD4
STSL
Sterolin-2
5-Fluorouracil [483], Fasudil [484]
None identified
None identified
None identified
None identified
None identified
Doxorubicin [394]
None identified
None identified
None identified
Bisantrene [485], Dasatinib [397], Doxorubicin [486],

Daunorubicin [486], Epirubicin[487], Flavopiridol [256],
Irinotecan/CPT-11 [264], Methotrexate [448], Mitoxantrone [486],
Nilotinib [397], SN-38 [264], Topotecan [488], Tyrosine kinase
inhibitors [321]
Apatinib [414], Curcumin [353], Curcumin [352],

Dofequidar [419], Elacridar/GG918/GF120918 [425],
Flavinoids [350], Fumitremorgin C [489], Gefitinib [490],
Ginsenosides [491], Imatinib Cyclosporin A [417], Ko143
[425], lapatinib [426], MK571 [425], Novobiocin [492],
Piperine [433], PK11195 [434], Polyphenols [351],
Tariquidar/XR-9576 [493], UR-COP269 [494],
VX-710/Biricodar [440], WK-X-34 [441]
None identified
None identified
None identified
None identified
None identified
None identified
Each ABC transporter is listed along with any known synonyms. Any chemotherapeutic agents shown to be transported via knockdown or labelling studies are
listed. Chemotherapeutic agents commonly used in the treatment of ovarian cancer are in bold. Additionally, substances which have been shown to inhibit the
ABC transporters are listed.
their tissue samples [57]. These findings indicate that the role
of ABCA2 in ovarian cancer should be further investigated.
2.1.3. ABCA3
ABCA3 is known for its role in production of pulmonary
surfactant in type 2 pneumocytes. ABCA3 has been shown
to be up-regulated in some leukemias and breast cancer

[52,54,58]. Silencing of ABCA3 in non-small-cell lung cancer cells resensitised the cells to cisplatin and paclitaxel
[59]. Additionally, Oiso et al. recently found ABCA3 was upregulated in cisplatin resistant human epidermoid carcinoma
cells compared to parental cells [48]. Furthermore, ABCA3
Fig. 1. The basic structure of ABC transporters. A typical ABC transporter consists of two transmembrane domains and two nucleotide binding domains.
However, variations exist on this basic structure. Some ABCC family members have three transmembrane domains and two nucleotide binding domains. Just
over a third of all ABC transporters are transcribed as half transporters, with a single transmembrane domain and a single nucleotide binding domain. It is
believed that the majority of these form homo- or hetero-dimers in order to form a complex capable of transport. ABCE1 has no TMDs.
226
Fig. 2. A typical transport process of an ABC transporter. ABC transporters are believed to exist in an inward facing conformation when not actively transporting,
i.e., with their TMD opening facing the interior of the cell. When a complex, such as a chemotherapeutic agent, is recognised by the TMDs, the NBDs dimerise,
powered by ATP hydrolysis, and trigger a change in the conformation of the transporter to the outward facing configuration, releasing the complex outside the
cell.
Fig. 3. Cartoon representations of known ABC exporter structures. Structures were downloaded from the RSCB Protein Databank and oriented and exported
using PYMOL [3133,35,3739].
was found to be up-regulated in cisplatin, paclitaxel, topotecan, and vincristine resistant ovarian cancer cells [60]. HPA
found medium to high ABCA3 expression in ovarian cancer cells in 7 of their 11 tissue samples [57]. These studies
suggest that ABCA3 may play a role in ovarian cancer drug
resistance mechanisms.
2.1.4. ABCA4
ABCA4 is well known for its role in Stargardt disease, an
inherited form of juvenile macular degeneration [12]. However, only a handful of studies so far have been undertaken
to determine its role in cancer. ABCA4 was found to be upregulated significantly in an induced MDR breast cancer cell
line [61]. Additionally, ABCA4 was found to be up-regulated
almost 2.5 fold in stage I epithelial ovarian cancer compared
with borderline ovarian tumours [62], which could make it
a useful marker for distinguishing between borderline and
early stage ovarian cancer. A recent study has found that
high ABCA4 expression was associated with chemotherapy

response in ovarian cancer patients [63].
2.1.5. ABCA5
Little is known about the physiological function of
ABCA5 since its discovery in 2003. ABCA5 was significantly
down-regulated in breast tumours compared with control
tissues [52] and was also recently identified as a putative
biomarker of osteosarcoma tumour stem cells [64]. It has also
been linked to the development of oesophageal cancer [65].
HPA found medium staining for ABCA5 in ovarian cancer
cells in all 11 of their tissue samples [57] and ABCA5 mRNA
was detected in undifferentiated ovarian carcinomas [53].
Furthermore, Hedditch et al. found that low expression levels
of ABCA5 was associated with shorter OS in serous ovarian cancer patients [45]. However, ABCA5 is up-regulated
in doxorubicin, paclitaxel, and vincristine resistant ovarian
cancer cells providing a possible link to drug resistance [60].
Further studies will determine whether ABCA5 is involved

in mediating drug resistance in ovarian cancer.
2.1.6. ABCA6
Very little is known about the physiological function
ABCA6. It has been proposed that may be involved in
macrophage lipid homeostasis [66] but there have been
limited studies in cancer. Whilst a study by Ohtsuki et al.
found no ABCA6 mRNA in a range of cancer cell lines
and tissues including ovarian cancer [53], other researchers
described increased ABCA6 expression in lymphoma cell
lines that exhibited a weak response to drug treatment
[67]. ABCA6 expression was significantly down-regulated
in breast tumours and ovarian serous papillary carcinomas compared with normal tissues [52,68]. Furthermore,
ABCA6 expression was found to be up-regulated in serous
ovarian tumours and associated with reduced OS [45], indicating that further investigation into this ABC transporter is
needed.
2.1.7. ABCA7
ABCA7 is most well-known for its link with Alzheimers
disease [65]. It was also reported to be up-regulated in pancreatic ductal adenocarcinoma and breast cancer [42,52].
Colorectal cancer patients with low ABCA7 transcript levels
had significantly shorter PFS [69]. ABCA7 mRNA expression
was shown to increase in head and neck squamous cell and
human epidermoid carcinoma cell lines in response to cisplatin and paclitaxel [48,70]. HPA found higher staining for
ABCA7 in all of their ovarian cancer tissues [57] but to date
no ovarian cancer studies investigating ABCA7 expression
have been published.
2.1.8. ABCA8
The function of ABCA8 is currently unknown, although
it has been postulated that it may play a role in myelin formation [71]. ABCA8 expression was reduced in ovarian cancers
compared to normal ovarian tissues [52,57]. ABCA8 was
also significantly down-regulated in a methotrexate, cisplatin,
doxorubicin, vincristine, topotecan, and paclitaxel-resistant
variant of the W1 ovarian cancer cell line [60]. In contrast,
ABCA8 expression was found to be positively associated with
gemcitabine resistance in ovarian cancer cell lines [72] and
significantly associated with reduced OS in serous ovarian
cancer patients [45]. This conflicting data indicates that further work is necessary to assess the exact role of ABCA8 in
ovarian cancer.
2.1.9. ABCA9
The function of ABCA9 remains unconfirmed; however it
may play a role in monocyte differentiation and lipid homeostasis [73]. Its role in cancer is poorly understood as only a
few studies have been published [52,74]. High expression
of ABCA9 was associated with significantly reduced survival in serous ovarian cancer patients [45]. ABCA9 was also
found to be hypermethylated before and after treatment with
227
DNA hypomethylating agent (decitabine) in ovarian cancer

patients with a PFS 6 months, but not in patients with <6
months PFS [75], indicating a possible role for ABCA9 in
ovarian cancer progression.
2.1.10. ABCA10
ABCA10 is perhaps the least investigated of the ABCA
family since its discovery in 2003. Its function and substrate are unknown, although its expression has been shown
to be regulated by cholesterol, indicating a possible role in
lipid transport similar to other members of the ABCA family
[76]. A single study showed that ABCA10 was significantly
down-regulated in breast tumours [52]. Normal ovarian tissue showed no reactivity for ABCA10 and only 5 out of 12
ovarian cancer tissue samples showed even low staining, suggesting ABCA10 may be down-regulated in ovarian cancer
[52]. There have been no other reports to date for ovarian
cancer.
2.1.11. ABCA12
Mutations of ABCA12 are the underlying cause for the
skin condition harlequin ichthyosis, the most severe variant
of autosomal recessive congenital ichthyosis [14]. ABCA12s
physiological function is thought to maintain the epidermal lipid permeability barrier by facilitating formation of
ceramide linoleic esters [77]. However, despite the vast number of studies on the role of ABCA12 in ichthyosis, there is
only a handful investigating its role in cancer. ABCA12 was
significantly up-regulated in breast and colorectal tumour tissues [52,69] and high expression was associated with poor
treatment response in breast cancer patients [44,52]. HPA
found moderate to high staining for ABCA12 in 8 of their 11
ovarian cancer tissue samples [57]. There have been no other
reports to date for ovarian cancer.
2.2. The ABCB family
2.2.1. ABCB1
ABCB1 (MDR1), also known as p-glycoprotein is the
most studied ABC transporter and first to be identified [78].
It is a 170 kDa protein localized at the apical surface of
many cells and is thought to play an important role in cell
detoxification [79,80]. ABCB1 transports large hydrophobic, uncharged, or slightly positively charged compounds
and plays a critical role in drug efflux and chemoresistance
in many malignancies [8183]. It transports chemotherapy
drugs including paclitaxel, doxorubicin, topotecan, docetaxel
but not platinums or cyclophosphamide [84] (Table 1).
ABCB1 positivity ranges from 7% to 92.8% across multiple ovarian cancer studies [8398] (Table 2). The largest
of these studies included 1036 primary ovarian cancers
and 2137 metastatic cancers which reported low ABCB1
expression (10% and 12% in primary and metastatic cancer, respectively) [92]. However, this study did not specify
the ovarian cancer subtypes examined or relate ABCB1
expression to survival outcome. Many studies have found
228
Table 2
Summary of ABCB1 studies in ovarian cancer tissue cohorts.
Cohort details
Type of analysis
Major findings
Ref.
Pre-treatment advanced stage (n = 5)

Subtype not known
Prior to treatment (n = 33)
Post chemotherapy (n = 24)
Immunohistochemistry
Antibody not known (only abstract available)
Immunohistochemistry (paraffin sections, two step
immunoperoxidase)
Monoclonal antibodies C219 and JSB-1
Immunohistochemistry (frozen sections)
C219 monoclonal antibody
5% cut point
Immunohistochemistry (paraffin, sections)
C219 monoclonal antibody
Semi-quantitative RT-PCR
ABCB1 expressed in 40% of cases
[85]
Pre-treatment (n = 21)
Subtypes not specified
Pre-treatment advanced stage (n = 20)
Serous (23)
Mucinous (7)
Endometrioid (9)
Clear cell (4)
undifferentiated (1)
Other (5)
Metastatic (3)
Serous (40)
Mucinous (5)
Endometrioid (4)
Undifferentiated (8)
Pre-treatment advanced (n = 89)
Serous (54)
Mucinous (9)
Endometrioid (7)
Clear cell (10)
Serous (24)
Mucinous (12)
Endometrioid (13)
Clear cell (6)
Serous (34)
Mucinous (1)
Endometrioid (7)
Clear cell (3)
Mixed (7)
Quantitative RT-PCR
Immunohistochemistry (frozen sections

Mouse monoclonal (MRK-16 &
JSB-1)
10% cutpoint
ABCB1 expression observed in 7% of cases and [86]

only in 2 patients that were clinically drug
resistant
ABCB1 expression in 71.4% of untreated cases [87]
and 61.5% after treatment with
platinum/cyclophosphamide
[84]
ABCB1 expression observed in 35% of cases
ABCB1 expressed in 65.2% untreated samples [111]
and 100% of tumours after treatment with
ABCB1 substrates
Highest ABCB1 expression was observed in
[107]
serous and mucinous subtypes
No relationship with chemotherapy response or
survival
[88]
ABCB1 expressed in 16% of cases.
survival
Immunohistochemistry (paraffin, microwave retrieval) ABCB1 expressed in 13% cases. ABCB1

Mouse Monoclonal JSB-1
expression not related to any clinical or
pathological parameters or patient outcome
[89]
Immunohistochemistry (paraffin)
Rabbit polyclonal (Oncogene Research products)
Cut point 30%
ABCB1 expressed in 27.6% of cases. No

relationship with survival
[90]
Quantitative RT-PCR
[99]
ABCB1 expressed in 35.6% of cases
ABCB1 expression associated with reduced PFS
Mucinous/Clear cell (89)
Other (69)
Pre-treatment advanced primary (n = 1036)
Metastatic (n = 2137)
Subtypes not known as only abstract
available
Immunohistochemistry (frozen) JSB-1 monoclonal

antibody
Cut point 10%
JSB1 mouse monoclonal
Serous
Pre-treatment advanced (n = 27)
Serous (90)
Clear cell (41)
Quantitative RT-PCR
ABCB1 expressed in 17.4% cases

survival
ABCB1 expressed in 12% primary cancers and
10% of metastatic lesions.
Survival analysis not performed
ABCB1 expressed in 25% of cases.
No relationship with chemotherapy response.
ABCB1 was increased in tumour tissues after
chemotherapy
ABCB1 undetectable in any tumour
Antibody details not known (only abstract available)
Quantitative RT-PCR
[91]
[92]
[93]
[190]
ABCB1 expressed in 96% cases

[100]
ABCB1 expression increased in non-responders
[94]
Immunohistochemistry (paraffin, microwave retrieval) ABCB1 expressed in 46.7% of serous and
Mouse monoclonal C494 (DAKO, Glostrup,
41.5% clear cell cancers.
Denmark)
No relationship with chemotherapy response in
Cut point 10%
either serous or clear carcinoma
229
Table 2 (Continued)
Cohort details
Type of analysis
Major findings
Ref.
Serous (57)
Mucinous (7)
Endometrioid (13)
Clear cell (16)
Pre-treatment and paired samples at
recurrence (n = 32)
Serous (26)
Clear cell (2)
Endometrioid (2)
Mixed (2)
Serous (18)
Mucinous (19)
Endometrioid (9)
Clear cell (8)
Other (5)
Serous (40)
Endometrioid (4)
Mucinous (1)
Others (5)
Pretreatment (n = 52)
Stage III serous
Immunohistochemistry (paraffin, microwave

retrieval)
C-19 goat polyclonal
Cut point 10%

ABCB1 more frequent in clear cell carcinoma
No relationship with survival
[95]

retrieval)
Mouse monoclonal c494 and c219 antibodies
0, 1+ vs 2+, 3+ staining
[96]
c494 antibody: ABCB1 expressed in 50% of
untreated samples and 75% of recurrent samples.
c219 antibody: ABCB1 expressed in 46.9% of
untreated and 21.9% recurrent samples.
ABCB1 expression could predict response to
paclitaxel and survival in recurrent samples.
ABCB1 expressed in 30.5%
[97]
No relationship with survival
Pre-treatment serous (n = 60)
Pre-treatment (n = 43) and post

chemotherapy (n = 30)
Serous (37)
Endometrioid (3)
Other (3)
Serous (86)
Endometrioid (42)
Clear cell (16)
Mucinous (14)
Other (15)
Serous (70)
Mucinous (23)
Endometrioid (8)
Clear cell (8)
Subtypes not indicated in abstract
Pre-treatment serous (n = 143)
All patients received 1st line paclitaxel
and carboplatin
Serous (83)
Endometrioid (14)
Mucinous (5)
Clear cell (6)

retrieval)
JSB-1
Quantitative RT-PCR
ABCB1 expression in 98% of cases. High

ABCB1 associated with reduced PFS
[495]

retrieval)
Clone MDR 88 (Biogenix)
Positive if membrane staining present
retrieval)
JSB-1 & C494
retrieval)
C219
Cut point: Histoscore >03
ABCB1 expressed in 92.8% of cases

High ABCB1 associated with reduced OS
[101]
ABCB1 expressed in 20% of cases using both

JSB-1 and C494. Increased ABCB1 expression
independent predictor of reduced OS.
High ABCB1 expressed in 53.5% of untreated
cases and 30% of cases after chemotherapy.
High ABCB1 significantly associated with
reduced PFS in untreated cases.
[83]
Quantitative RT-PCR

reduced PFS but OS
[102]

retrieval, immunofluorescence)
Rabbit anti human sc-1517-R (Santa Cruz)
Cut point 25%
ABCB1 expressed in 80% of cases. High

ABCB1 significantly associated with tumour
stage, grade and disease relapse
[103]
Antibody not known (only abstract available)
ABCB1 expressed in 57.5% of cases. High

[104]
ABCB1 expression significantly associated with
OS
[105]
shorter PFS
Quantitative RT-PCR
(paraffin, microwave retrieval)
MDR88 (BioGenex)
Cut point 85%
ABCB1 expression associated with PFS

(P = 0.053)
References in bold indicate studies that found relationships with chemotherapy response or survival outcome.
[98]
[106]
230
a relationship between high ABCB1 mRNA or ABCB1 protein levels and poor ovarian cancer outcome [83,96,98106]
whilst several others have not [8891,93,94,97,107]. The
reason for this inconsistency is not clear but possible reasons may be due to small cohort size and the inclusion of
different ovarian cancer subtypes and stages in the analysis. Three studies that investigated expression in the serous
subtype only did report a significant relationship with high
ABCB1 protein or ABCB1 mRNA levels and poor patient
outcome [83,101,105]. However, clinically validated assays
for ABCB1 detection in tissues have not been established and
the variability may also be due to the use of different antibodies and methods used for assessment. Many antibodies
are not specific for ABCB1 and cross react with pyruvate
carboxylase (JSB-1) and other ABC transporter proteins
[108].
Increased ABCB1 mRNA and ABCB1 protein has been
seen in many drug resistant ovarian cancer cell lines
[60,82,84,109,110]. However, several studies found no difference in ABCB1 protein or ABCB1 mRNA levels in tissues
from treated versus untreated ovarian cancers [86,87,96]
whilst others researchers reported marked differences following treatment [93,96,111]. Several studies have found
that ABCB1 is expressed in ovarian tumours which have
been exposed to its substrates, such as paclitaxel, but not
in chemonaive tumours or tumours exposed to non ABCB1
substrates including cisplatin [111,112]. Our own data concurs with these findings as we found no ABCB1 expression
in ovarian cancer cells treated with the platinum, carboplatin
[113]. Our recent immunohistochemistry studies detected
minimal ABCB1 protein in ovarian cancer tissues collected
at surgery prior to chemotherapy treatment (Fig. 4A and B)
but found increased ABCB1 levels in tumour tissues from
patients that received neoadjuvant carboplatin and paclitaxel treatment (Fig. 4D). Minimal ABCB1 expression was
observed in a patient that received neoadjuvant single carboplatin treatment (Fig. 4C). However, high ABCB1 levels were
present in recurrent ovarian cancers from patients that had
received both carboplatin and paclitaxel treatment (Fig. 4E
and F).
Whilst some earlier studies reported that ABCB1 polymorphisms were associated with ovarian cancer outcome
and toxicity to taxane and platinum based chemotherapy
[114119], a recent systemic review found no consistent association with any ABCB1 SNPs and clinical outcome [120].
A large comprehensive study looking at 21 different ABCB1
SNPS in 4025 patients did not find any association between
ABCB1 SNPs and PFS or OS [105]. These findings were also
confirmed in an independent study of over 10,000 ovarian
cancer cases [121]. Several ABCB1 SNPs have been reported
to alter paclitaxel clearance [116,122], substrate specificity
[123] and neutrophil toxicity [124] but other studies found
no relationship with toxicity and neutropenia [125,126]. The
relationship of ABCB1 SNPs with toxicity needs to be also
assessed in the large well defined clinical cohorts like survival
outcome.
2.2.2. ABCB2 and ABCB3

ABCB2 and ABCB3, also known as TAP-1 and TAP2, respectively, form a heterodimer (Fig. 1) to form TAP
(transporter associated with antigen processing) which delivers cytosolic peptides into the endoplasmic reticulum (ER),
where they bind to nascent MHC class I molecules. TAP is
part of the peptide-loading complex (PLC) along with 2
microglobulin and other molecules which acts to keep hold
of MHC molecules until they have been fully loaded with
peptides ready for presentation to cytotoxic T lymphocytes
[98,104,238,263].
Many studies have shown that low ABCB2 and ABCB3
levels in various cancer types are linked to poor outcome,
suggesting that their down-regulation may aid cancer cells to
evade immune detection [44,127136]. ABCB2 is also downregulated in metastatic cancers compared to primary cancers
[137139]. In ovarian cancer high ABCB2 and ABCB3
expression was associated with low grade cancers, negative
lymph node status and increased OS [140142]. However,
another study found no relationship between ABCB2 and
survival outcome [143].
There is also some evidence that ABCB2 and ABCB3 are
linked with chemotherapy resistance. ABCB2 is increased
in acute myeloid leukaemia cells (AML) compared with
healthy bone marrow [55] and both ABCB2 and ABCB3 were
up-regulated in breast cancers following treatment with neoadjuvant chemotherapy [52]. Another study by Xu et al. has
suggested that ABCB2 may be involved in the resistance
of pancreatic cancer cells to gemcitabine [144]. Furthermore, ABCB3 is increased in recurrent ovarian cancers [145].
Our own preliminary analysis showed variable ABCB3 protein levels in ovarian cancer tissues. Tissues from patients
after neoadjuvent carboplatin treatment (Fig. 4C) and after
adjuvant carboplatin + paclitaxel chemotherapy at recurrence
(Fig. 4E) had higher ABCB3 levels compared with tissues
from untreated ovarian cancers (Fig. 4A and B). Further work
exploring the role of the TAP heterodimer in ovarian cancer
cells is required.
2.2.3. ABCB4
ABCB4 (also known as MDR3) is normally involved
in the transport of phospholipids from the liver hepatocytes into bile [146]. It is often considered a homologue of
ABCB1; however, very little is known about its role in cancer.
ABCB4 protein is up-regulated in soft tissue sarcomas [147]
and increased levels are associated with poor outcome in
patients with acute leukaemia [148]. ABCB4 is up-regulated
in pancreatic ductal adenocarcinoma and is thought to contribute its poor treatment response to chemotherapy treatment
[42] but high expression in lung cancer cells suppressed
their growth [149]. ABCB4 was found to be up-regulated
16-fold in paclitaxel resistant ovarian cancer cell lines compared with the parental cell line and siRNA knockdown of
ABCB4 increased the sensitivity to paclitaxel [82]. Furthermore, ABCB4 was up-regulated 176-fold in doxorubicin and
147-fold in vincristine resistant sublines of ovarian cancer
231
Fig. 4. ABC transporter expression in ovarian cancer tissues. Formalin fixed paraffin sections (5 m) were immunostained with antibodies to ABCB1 (mouse
monoclonal, clone F4, 1/1200, P7965, Sigma Aldrich), ABCB3 (rabbit polyclonal 1/750, Ab130414, Abcam), ACBC2 (mouse monoclonal clone M2 I-4, 1/50,
Abcam) and ABCG2 (mouse monoclonal clone BXP-21, 1/100, ab3380, Abcam) using citrate buffer microwave retrieval as previously described [496]. (A)
Untreated stage IIIC serous ovarian carcinoma. (B) Untreated stage IIIC serous ovarian carcinoma. (C) Stage IV serous carcinoma treated with neoadjuvent
carboplatin alone. (D) Stage III peritoneal carcinoma treated with neoadjuvent carboplatin + paclitaxel. (E) Recurrent mucinous ovarian carcinoma treated
with carboplatin + paclitaxel. (F) Recurrent endometrioid ovarian carcinoma treated with carboplatin + paclitaxel. Bar = 100 m. All images are at the same
magnification.
cells [60], providing evidence that ABCB4 may play a similar

role in MDR like ABCB1.
2.2.4. ABCB5
The exact function of ABCB5 remains unknown, although
it has been found to be increased in melanoma [150] and
placental tumours [151]. High ABCB5 expression is an independent prognostic factor for predicting oral squamous cell
carcinoma recurrence [152]. It has been linked to chemoresistance in melanoma [153], liver cancer [154], breast cancer
[155], and colon cancer [156]. c-MYC was shown to bind to

the ABCB5 promoter region and a c-MYC inhibitor increased
colon cancer cell sensitivity to fluorouracil [157]. ABCB5 has
been shown to transport doxorubicin and topotecan in non
ovarian cancer cells (Table 1) but its role has not yet been
confirmed in ovarian cancer cells.
2.2.5. ABCB6
ABCB6 is involved in hematopoesis and is a mitochondrial transporter [158]. It is highly expressed in most normal
232
tissues. ABCB6 is up-regulated in colorectal cancer [69],

glioma [159], hepatocellular carcinoma [51], and melanoma
cells [136]. Furthermore, ABCB6 was significantly increased
in residual breast cancers after chemotherapy [44]. ABCB6
was found to be up-regulated 15-fold in paclitaxel resistant
ovarian cancer cells compared with the parental cell line
[160]. Additionally, ABCB6 was found to be up-regulated
in cisplatin, doxorubicin, methotrexate, paclitaxel, topotecan, and vincristine resistant sublines of ovarian cancer cells
[60], indicating a role for ABCB6 in ovarian cancer drug
resistance.
2.2.6. ABCB7
A mutation of the ABCB7 gene is the underlying cause
of X-linked sideroblastic anaemia with ataxia [13]. Only a
handful of studies have reported a possible role of ABCB7 in
cancer. ABCB7 expression was found to be high in retinoblastoma cells [161]. A thesis covering a wide range of ABC
transporters found that ABCB7 mRNA levels were increased
in a platinum-resistant ovarian carcinoma cell line [162],
however further work exploring the role of ABCB7 in ovarian
cancer is required.
2.2.7. ABCB8
Whilst the precise function of ABCB8 is unknown, it has
recently been suggested to be involved in mitochondrial iron
export essential for baseline cardiac function [163]. Similar
to ABCB7, there has been very little research into the role of
ABCB8 in cancer. ABCB8 has been shown to be up-regulated
in several drug resistant cell lines [164]. It is also known
that ABCB8 transports doxorubicin in melanoma, breast, and
ovarian cancer cells [165]. To date no ovarian cancer studies
investigating ABCB8 expression have been published.
2.2.8. ABCB9
ABCB9 translocates a broad spectrum of peptides from
the cytosol into the lumen of lysosomes [166]. It is often
called TAP-like protein, due to its antigen presenting role.
Whilst ABCB9 has not been studied as thoroughly as ABCB2
and ABCB3 which make up the TAP complex, it is highly
expressed in most normal tissues but to a lesser extent in most
cancer tissues, including ovarian cancer [57]. A very recent
study showed that ABCB9 confers resistance to cisplatin in
lung cancer cells via the micro RNA miR-31 [167] which
has also been shown to confer resistance to chemotherapyinduced apoptosis in prostate and colon cancer [168,169].
However, ABCB9 has not been studied in ovarian cancer to
date.
2.2.9. ABCB10
ABCB10 one of the three ABC transporters found in the
inner membrane of mitochondria, is essential for erythropoiesis [170] and is thought to act as a homodimer (Fig. 1).
Whilst little is known about the role of ABCB10 in cancer,
ABCB10 expression has been associated with cisplatin resistance in a range of cancer cell lines [171,172]. Gillet et al.
also found that ABCB10 mRNA levels in peritoneal effusions could predict shorter PFS in ovarian cancer patients
[173]. Further studies are required to understand the role of
ABCB10 in ovarian cancer.
2.2.10. ABCB11
ABCB11 is the bile salt exporter protein (BSEP). Thus,
ABCB11 research has so far been focused on liver disease.
BSEP disease is caused by a wide range of mutations in
ABCB11 which result in ABCB11 deficiency and a higher
risk of liver cancer especially in children [174]. ABCB11 is
up-regulated in pancreatic ductal adenocarcinoma [42] but
down-regulated in breast tumours [52]. ABCB11 is often
called the sister to Pgp/ABCB1 and has been shown to confer
some level of resistance to paclitaxel [175] but has not been
studied in ovarian cancer.
2.3. The ABCC family
The largest sub-family of ABC transporters is the ABCC
family (also known as multidrug resistance protein/MRP
family ABCC1-12). This ABC transporter family transports hydrophobic anionic conjugates and exports uncharged
hydrophic compounds.
2.3.1. ABCC1
In contrast to ABCB1, which extrudes xenobiotics into
bile, intestine, and blood for terminal elimination from the
body, ABCC1 (MRP-1) is a basolateral transporter that
allows movement of compounds away from luminal surfaces and into tissues that lie beneath the basement membrane
[176]. Its structure is similar to ABCB1 but it has an additional
5 transmembrane helices at the N-terminus of the protein,
creating a third TMD, MSD0 (Fig. 1). The MSD0 domain
of ABCC1 is grossly dispensable for its transport function
however the cytoplasmic loop connecting the third TMD is
required for its activity [177].
Unlike ABCB1, ABCC1 does not seem to have a critical
role in the bodys normal elimination of toxins, which may
make it a more suitable therapeutic target. Its physiological
function is thought to protect cells from chemical toxicity
and oxidative stress and to mediate inflammatory responses
[178]. ABCC1 transports vinca alkaloids, anthracyclines,
methotrexate, leukotriene C4, and substrates conjugated with
glucaronide, sulphate, or glutathione [179184].
ABCC1 has been found to be increased in a range of
cancers including hepatocellular carcinoma [51], paediatric
acute lymphoblastic leukaemia [185], colorectal cancers
[69], nasopharyngeal carcinoma [186], pancreatic ductal adenocarcinoma [42], and breast cancer [52]. ABCC1 positivity
ranges from 22.2% to 68.0% across multiple ovarian cancer studies [88,90,91,114,187,188] (Table 3). However, there
is a discrepancy between studies indicating ABCC1 mRNA
or ABCC1 protein levels can predict poor chemotherapy
response and reduced survival [90,106,145,187190] which
was not reported by other groups [88,91,94,99,100,114]. The
233
Table 3
Summary of ABCC1 studies in ovarian cancer tissue cohorts.
Cohort details
Type of analysis
Major findings
Ref.
Serous (40)
Mucinous (5)
Endometrioid (4)
Serous (34)
Mucinous (1)
Endometrioid (7)
Other (10)
Serous (23)
Muncinous (9)
Other (69)
Serous (24)
Mucinous (12)
Endometrioid (13)
Other (9)
Serous
Immunohistochemistry (frozen sections

Mouse monoclonal MrPr1
ABCC1 expressed in 68% of cases.

survival
[88]
Quantitative RT-PCR
ABCC1 expressed in 100% of cases. ABCC1

expression was not associated PFS
[99]
Quantitative RT-PCR
ABCC1 expressed in 97% of cases. ABCC1 levels

were 2-fold higher in non-responders compared to
responders
ABCC1 expressed in 44% cases
No relationship with chemotherapy response or PFS
[189]
ABCC1 expressed in 22.4% of cases. No

relationship with survival
[90]
High ABCC1 expressed in 50% of serous carcinoma

and significantly associated an unfavourable
outcome and reduced PFS
No relationship with chemotherapy response
[190]

retrieval)
Rabbit polyclonal C-10 (Santa Cruz)
Cut point 10%
Rabbit polyclonal C-10 (Santa Cruz)
Cut point 5%
Quantitative RT-PCR
ABCC1 expressed in 27.8% of serous and 19.5%

clear cell cancers.
No relationship with chemotherapy response in
either cancer type
ABCC1 expressed in 38.3% of cases.
No relationship with chemotherapy response or PFS
[94]
ABCC1 expressed in 84.8% of cases
[187]

retrieval)
Rat monoclonal MRPr1
Histoscore 6
Quantitative RT-PCR
High ABCC1 expressed in 55% of cases. High

ABCC1 expression associated with high tumour
grade, higher stage and reduced OS.
ABCC1 expression was increased in recurrent
cancers compared to primary cancers and benign
tumours
[145]
Immunohistochemistry (paraffin, heat retrieval)

Mouse monoclonal clone QCRL-2
ABCC1 expression not associated with survival

outcome
[197]

retrieval)
Rat monoclonal MRPr1
Cut point 10%
ABCC1 expressed in 30% of cases. ABCC1

expression significantly associated with tumour
grade
[188]
Pre-treatment advanced
(n = 27)
Serous (25)
Clear cell (1)
Endometrioid (1)
Serous (90)
Clear cell (41)
Serous (50)
Endometrioid (10)
Serous (78)
Non-serous (37)
Serous (40)
Endometroid (7)
Mucinous (1)
Others (2)
Recurrent disease (n = 50)
Serous (44)
Endometroid (2)
Mucinous (1)
Others (3)
Serous (34)
Non-serous (13)
Serous (83)
Clear cell (12)
Endometrioid (12)
Mucinous (6)
Others (2)
Immunohistochemistry (frozen)
MRPm6 monoclonal antibody
Cut point 10%
MRPm6 monoclonal antibody
Cut point 30%
Quantitative RT-PCR
Quantitative RT-PCR
[91]
[100]
[114]
234
Table 3 (Continued)
Cohort details
Type of analysis
Major findings
Ref.
Serous (83)
Endometrioid (14)
Mucinous (5)
Clear cell (6)

retrieval)
33A6 (Novacastra)
Cut point 85%
High ABCC1 expression associated reduced PFS

and OS
[106]
reason for this inconsistency is not clear but a possible reason may be due to the inclusion of different ovarian cancer
subtypes and stages in the analysis. In addition the use of
different antibodies and methods may also contribute to the
variance. Like ABCB1, ABCC1 SNPs were not associated
with ovarian cancer outcome [125].
2.3.2. ABCC2
ABCC2 (MRP-2), the canalicular multispecific organic
anion transporter (cMOAT), is 190 kDa and has 49% AA
identity with ABCC1 [191]. It is thought to have a physiological role as an organic anion pump in the liver and play a role
in detoxification of alkylating agents in the apical epithelium of the liver and kidney [192,193]. ABCC2 positivity
varies from 16% to 100% in ovarian cancer tissue cohorts
[91,114,194,195] (Table 4). The largest cohort examined to
date included 115 ovarian cancer tumours [91]. There are
studies which described ABCC2 protein or ABCC2 mRNA
levels to be associated with outcome [145,196,197] while
others did not [91,100,190,195]. The reason for this inconsistency is not clear but possible reasons may due to small cohort
size and the inclusion of different ovarian cancer subtypes in
the analysis. Another possible explanation for this inconsistency may lie in the localisation of ABCC2 within the cell.
Surowiak et al. found that higher nuclear ABCC2 levels both
before and after chemotherapy resulted in cisplatin resistance
and shorter survival time. However, total and cytoplasmic
ABCC2 levels were not associated with outcome [196].
Our data concurs with these findings as we found increased
ABCC2 expression in ovarian cancer cells treated with carboplatin [113]. Furthermore, minimal ABCC2 protein was
detected by immunohistochemistry in ovarian cancer tissues
collected at surgery prior to chemotherapy treatment (Fig. 4A
and B) but increased nuclear ABCC2 levels were observed in
tumour tissues from patients that received either neoadjuvant
single carboplatin (Fig. 4C) or carboplatin + paclitaxel treatment (Fig. 4D). High nuclear ABCC2 levels were also present
in a recurrent ovarian cancer from a patient that had received
adjuvant carboplatin + paclitaxel treatment (Fig. 4E). As for
ABCB1 and ABCC1, ABCC2 SNPs appear not be associated
with ovarian cancer outcome [125,198].
2.3.3. ABCC3
ABCC3 (MRP-3) has 58% AA identity with ABCC1 [191]
and transports organic conjugates and nucleosides [180].
ABCC3 expression is increased in lung cancer [199], breast
cancer [200], cervical cancer [201], hepatocellular carcinoma

[51], and pancreatic cancer [42]. Less is known about the role
of ABCC3 in ovarian cancer compared with ABCC1 and
ABCC2. ABCC3 expression correlates with ABCC1 [190]
and found to be higher in clear cell than serous papillary carcinomas [190]. ABCC3 was localized in the plasma membrane
and cytoplasm and ABCC3 mRNA levels were significantly
lower in ovarian cancer patients with a PFS period 2 years
[190]. ABCC3 was significantly elevated in recurrent ovarian
cancers [145] as well as in late stage ovarian cancers compared with early stage lesions [202]. Whilst studies have not
yet been undertaken to determine whether ABCC3 transports
ovarian cancer chemotherapy drugs, our own recent studies
show that treatment of ovarian cancer cells with carboplatin
increases the expression of the extracellular matrix component, hyaluronan, which in turn increased the expression of
ABCC3 in cells expressing the hyaluronan receptor, CD44
[113].
2.3.4. ABCC4
ABCC4 has the ability to transport molecules involved in
cellular signalling including cyclic nucleotides, eicosanoids,
urate, and conjugated steroids [203]. ABCC4 is increased
in a range of cancer including hepatocellular carcinoma
[51], breast cancer [52], melanoma [136] and lung cancer
[204]. ABCC4 protein is increased in oesophageal [205] and
prostate cancer [206]. ABCC4 has recently been linked with
increased cancer cell proliferation [204,205,207,208]. Little
is known about the role of ABCC4 in ovarian cancer but Bagnoli et al. showed that high ABCC4 expression was associated
with PFS [188], and Beretta et al. suggested that ABCC4 glycosylation may play a role in ovarian cancer chemoresistance
[209].
2.3.5. ABCC5
ABCC5 (MRP-5) is known to transport organic conjugates and nucleosides [180]. Increased ABCC5 expression
has been associated with hepatocellular carcinoma [51],
nasopharyngeal carcinoma [186], pancreatic ductal adenocarcinoma [42], and breast cancer [44]. Only one study
currently has shown a potential role for ABCC5 in ovarian
cancer. Whilst ABCC5 expression was not associated with
histo-pathological parameters or PFS [210], it was found to
be elevated in late stage ovarian cancer patients compared
with early stage ovarian cancer [202].
235
Table 4
Summary of ABCC2 studies in ovarian cancer tissue cohorts.
Cohort details
Type of analysis
Major findings
Ref.
Pre treatment (n = 115)

Other (69)
Pre treatment (n = 17)
Immunohistochemistry (frozen)
Mouse monoclonal cloneM2 III-6
Cut point 10%
Immunohistochemistry (paraffin, heat
retrieval)
Rabbit polyclonal EAG5 &
Mouse monoclonal clone M2 III-6
Quantitative RT-PCR
16% positive
No relationship with 1st line chemotherapy
response or PFS
94.1% positive with EAG5 antibody
100% positive with M2-III-6 antibody
[91]

ABCC2 expression was not associated with
chemotherapy response or PFS.
ABCC2 expressed in 48.3% of cases.
or PFS
ABCC2 expressed in 56% of platinum
sensitive tumours and 235 of platinum
resistant tumours. ABCC2 expression not
correlated with platinum response
[100]

retrieval)
Mouse monoclonal clone M2 I-4
Cut point not indicated
Increased nuclear ABCC2 expression was

associated with reduced PFS and OS.
[196]
Quantitative RT-PCR
ABCC2 expression was increased in

recurrent cancers compared to primary
cancers and benign tumours
[145]

retrieval)
Cut point 10%
High ABCC2 expression associated with

reduced PFS
[197]
Advanced pre treatment (n = 27)

Serous
Serous (50)
Endometrioid (10)
Platinum sensitive (9)
Serous (9)
Platinum resistant (13)
Serous (9)
Clear cell (1)
Mucinous (1)
Endometrioid (1)
Serous (35)
Endometrioid (3)
Others (3)
Serous (40)
Endometroid (7)
Mucinous (1)
Others (2)
Recurrent disease (n = 50)
Serous (44)
Endometroid (2)
Mucinous (1)
Others (3)
Serous (34)
Non-serous (13)
Quantitative RT-PCR
Rabbit polyclonal H-17 (Santa Cruz)
Cut point 5%
retrieval)
[194]
[190]
[114]
[195]
2.3.6. ABCC6
ABCC6 is best known for its mutations causing the softtissue mineralisation in pseudoxanthoma elasticum due to a
decrease in the release of ATP in the liver by ABCC6 leading
to reduced production of the mineralization inhibitor inorganic pyrophosphate [22]. Whilst it has been shown that
ABCC6 can transport a range of cancer drugs (Table 1),
there is little known about the role of ABCC6 in cancer
chemoresistance. There have been suggestions that ABCC6
is coamplified with ABCC1 because of its close location on
the same chromosome rather than having a specific regulatory control [211]. ABCC6 has, however, been shown to be
up-regulated in breast cancer [52] and it is part of a methylation profiling test 11-gene set which can predict bladder
cancer with 87% accuracy [212]. ABCC6 was found to be upregulated in mucinous ovarian adenocarcinomas compared
with benign mucinous cystadenomas [213]. ABCC6 has also

been shown to be up-regulated in paclitaxel and topotecan
resistant sublines of ovarian cancer cells [60].
2.3.7. ABCC7
ABCC7 is a chloride channel most commonly known
as cystic fibrosis transmembrane conductance regulator
(CFTR). ABCC7 mutations are responsible for creating
excess mucus found in the lungs in cystic fibrosis patients
[11]. Whilst no drug transport role for ABCC7 has been
reported, ABCC7 expression is increased in cervical cancer
[214] and ABCC7 mutations have been linked with pancreatic cancer [215]. However, low expression was associated
with advanced stage, lymph node metastasis and poor survival in non-small cell lung cancer patients [216] ABCC7
mRNA and protein expression has also been associated with
236
breast cancer treatment response [44,217] and tumour growth

suppression in prostate cancer [218]. ABCC7 expression has
been associated with increased oestrogen production and is
reduced in patients with polycystic ovary syndrome [16]. A
single study demonstrating that high ABCC7 expression was
associated with FIGO stage, poor histopathological grade and
serum CA125 links ABCC7 to ovarian cancer [219].
2.3.12. ABCC12
As one of the more recently discovered ABC transporters,
ABCC12 is poorly understood and its function is unknown.
ABCC12 expression is up-regulated in hepatocellular carcinoma [51] and breast cancer [52,226], but no studies
involving ovarian cancer have been reported to date.
2.4. The ABCD family
2.3.8. ABCC8
ABCC8 (sulfonylurea receptor 1/SUR1) is best known as
a sensor of intracellular levels of ATP and ADP and facilitates
the open or closing its associated KATP channel [220]. It is the
target of the sulfonylurea class of antidiabetic drugs which
promote insulin release from pancreatic beta cells. Whilst it
has not been reported to be involved in chemoresistance, it
has been associated with more aggressive cervical cancers
[221], high grade breast cancers [52], and brain metastases
[222]. No studies to date, have reported a role for ABCC8 in
ovarian cancer.
2.3.9. ABCC9
Splice variants arising from a single ABCC9 gene give
rise to SUR2A and SUR2B which like ABCC8 interacts
with the KATP channel in beta cells of the pancreas. Most
recently, ABCC9 mutations have been shown to result in
Cant syndrome, a rare genetic disease that results in bone
abnormalities, increased body hair, and an enlarged heart
[18]. ABCC9 variants have also been linked to the duration of
sleep required by individuals to feel rested [223]. Currently,
no studies link ABCC9 to any cancer.
2.3.10. ABCC10
ABCC10 is a 170 kDa protein that is localized on the
basolateral cell membrane which is well known as a broad
xenobiotic transporter (Table 1). ABCC10 has been associated with myeloid leukaemia [55], hepatocellular carcinoma
[51], pancreatic ductal adenocarcinoma [42], breast cancer
[52], as well as low grade colorectal tumours [69]. The
ABCC10 gene is hypermethylated in ovarian cancer patients
with a longer PFS [75]. Furthermore, ABCC10 expression
levels are increased in ovarian cancer xenograft tumours following treatment with doxetaxel [224]. Given the ability of
ABCC10 to efflux ovarian cancer therapeutics, further studies
to examine its role in chemoresistance are warranted.
2.3.11. ABCC11
A SNP in the ABCC11 gene is responsible for determination of human earwax type and presence of underarm odour
[225]. Despite having been found to transport a variety of
chemotherapeutic agents (Table 1), its role in cancer remains
relatively unexplored. ABCC11 expression is increased in
hepatocellular carcinoma [51], and breast cancer [44,52], but
no studies involving ovarian cancer have been reported.
The ABCD family (ABCD1-4) are peroxisomal halftransporters [227] (Fig. 1) whose mutations lead to impaired
peroxisomal beta-oxidation and accumulation of saturated
very long-chain fatty acids in tissues and body fluids associated with X-adrenoleukodystrophy, an inherited disorder
of peroxisomal metabolism, biochemically characterised by
accumulation of saturated very long chain fatty acids [15].
2.4.1. ABCD1
As so many of the ABC half transporters are shown to
dimerise to function, it was assumed that the ABCD transporters also formed dimers. Cell FRET analysis showed that
ABCD1 forms a homodimer, and can form a heterodimer
with ABCD3 [228]. Whilst little is known about the role of
ABCD1 in cancer, ABCD1 has been reported to be downregulated in renal cancer [229] and to be up-regulated in
melanoma [74] and breast cancer [52]. To date, there have
been no studies investigating the role of ABCD1 in ovarian
cancer.
2.4.2. ABCD2
ABCD2 has a functional redundancy with ABCD1. However, studies have also suggested that ABCD2 has a specific
role in lipid metabolism [230]. ABCD2 has only recently
become a subject of investigation in cancer and its role in
cancer remains undefined. ABCD2 expression is significantly
down-regulated in breast cancer and patients with higher
ABCD2 mRNA levels were more likely to respond to treatment [52]. ABCD2 has been shown to be up-regulated in
a topotecan resistant ovarian cancer subline [60] and high
ABCD2 expression correlated with poor ovarian cancer OS
[173].
2.4.3. ABCD3
ABCD3 is one of the most abundant peroxisomal
membrane proteins. Cell FRET analysis has shown that
ABCD3 forms a homodimer as well as a heterodimer with
ABCD1.[228] The ABCD3 expression is significantly upregulated in breast cancer [52] and associated with prostate
cancer aggressiveness [231,232]. ABCD3 is part of a 9-gene
panel along with ABCC3 that can predict non-small cell lung
cancer diagnosis with 99.75% predictive accuracy [233]. Furthermore, a recent conference abstract suggests that silencing
ABCD3 in a prostate cancer cell line resulted in increased
sensitivity to paclitaxel [232]. As paclitaxel is a key ovarian cancer drug these findings suggest that further studies
examining its role in ovarian cancer chemoresistance are

warranted.
2.4.4. ABCD4
ABCD4 has recently been shown not to be a peroxisomal
membrane protein but to reside in the ER. It has a 2527%
AA identity with the other three ABCD proteins but lacks
an N-terminal domain [234]. ABCD4 mutations have also
recently been shown to be involved in a lysosomal vitamin
B12 disorder [235]. There is a scarcity of studies investigating
the role of ABCD4 in cancer. A recent gene expression study
showed that the ABCD4 gene is significantly down-regulated
in breast tumours [52]. No studies to date, have reported a
role for ABCD4 in ovarian cancer.
2.5. The ABCE family
2.5.1. ABCE1
The only existing ABCE transporter, ABCE1/RLI, is
highly expressed in human lung adenocarcinoma tissues and
metastatic lymph nodes [236]. ABCE1 is a unique ABC
transporter as it has no TMDs and is therefore more akin to
an ABC-type ATPase than an ABC transporter. The structure of non-human ABCE1 has been solved [35] and it
likely plays a role in mRNA translation [237]. ABCE1 is
up-regulated in colorectal cancer [69], breast cancer [52],
melanoma [136], and hepatocellular carcinoma [51]. It has
been associated with proliferation, motility, and invasiveness
of oesophageal cancer cells [238]. Certain mutations are associated with prostate cancer [239], and ABCE1 siRNA knock
down inhibited the proliferation, invasiveness of small cell
lung cancer cells [240]. There have been no ovarian cancer
studies to date investigating ABCE1 expression.
2.6. The ABCF family
The ABCF transporters also do not have transmembrane
domains. They are similarly thought to play a role in mRNA
translation [237].
2.6.1. ABCF1
The ABCF1 gene is up-regulated in childhood T-cell acute
lymphoblastic leukaemia [54], and colorectal cancer [241],
as well as liver cancer where it was associated with poor outcome [242]. ABCF1 is up-regulated in breast cancer [52]
and is part of a six gene signature which can be used to
predict breast cancer patient outcome [243]. A single study
investigating the role of ABCF1 in ovarian cancer found a 3fold increase in ABCF1 in high grade stage I serous ovarian
carcinoma compared with normal tissue [62].
2.6.2. ABCF2
ABCF2 expression is significantly increased in melanoma
[136]. In breast cancer increased expression is associated with
treatment response and negatively associated with metastasis
[44,69,244]. Low ABCF2 expression was also found to be
237
an independent prognostic factor for survival in cervical cancer [245]. In ovarian cancer, it has been shown that ABCF2
is up-regulated after chemotherapy in high grade epithelial
ovarian cancers when compared with matching tissue before
treatment [246]. Interestingly, Tsuda et al. showed that levels
of ABCF2 mRNA and protein were increased in clear cell
compared with serous ovarian carcinomas [247] suggesting
a possible reason why clear cell carcinomas have a poorer
prognosis and are often more chemoresistant [94,248,249].
However, a later study showed that whilst ABCF2 expression was detected in the majority of clear cell ovarian cancer
patients it was not associated with clinical stage, response
to chemotherapy, or outcome [250]. Furthermore, a study
by Auner et al. did not find ABCF2 to be elevated in recurrent ovarian cancer [145]. These conflicting reports indicate
that further work is necessary to elucidate whether or not
ABCF2 plays any role in ovarian cancer progression and
chemoresistance.
2.6.3. ABCF3
ABCF3 is the least studied member of the ABCF family.
ABCF3 has been reported to be significantly up-regulated
in breast cancer [52], melanoma [136], and cervical cancer
[251]. No studies have linked ABCF3 to ovarian cancer.
2.7. The ABCG family
The ABCG family are half transporters thought to homoor hetero-dimerise in order to function as lipid transporters
(Fig. 1).
2.7.1. ABCG1
ABCG1 is the human homologue of the Drosophila white
gene, and is involved in the transport of cholesterol and phospholipids. It is up-regulated in breast cancer [52], pancreatic
ductal adenocarcinoma [42] and prostate cancer [252]. The
ABCG1 gene is hypermethylated before and after decitabine
treatment in ovarian cancer patients with longer survival [75].
Further studies are required to understand its role in ovarian
cancer.
2.7.2. ABCG2
ABCG2 is also known as the breast cancer resistance
protein (BCRP) or the mitoxantrone transporter (MXR1).
ABCG2 plays a protective role in the mammary glands
and can concentrate toxins released into breast milk [253].
ABCG2 is also localized in the placenta where it effluxes
xenobiotics and toxic endogenous compounds to protect
the developing foetus [254]. It has also been shown to
efflux urate and ABCG2 mutations have been linked to gout
[255]. ABCG2 is up-regulated in a wide range of cancers,
including nasopharyngeal carcinoma [186], pancreatic ductal adenocarcinoma [42], breast cancer [256], adenoid cystic
carcinoma [257], esophageal cancer [258], and tongue cancer
[259].
238
ABCG2 is a marker of ovarian cancer stem cells and

highly expressed in side population (SP) cells and ovarian
cancer spheroids which have higher chemoresistance to cisplatin or paclitaxel [260,261] (see Cancer stem cells and
ABC transporters section below). Like ABCB1, there has
been some controversy whether ABCG2 SNPs are associated
with ovarian cancer outcome. One study found no relationship [125] whilst another study found an ABCG2 variant to
be associated with longer PFS [198]. Interestingly an ABCG2
SNP was associated with increased oral bioavailability of the
ABCG2 substrate, topotecan [262]. Two polymorphic loci in
the ABCG2 promoter were associated with lower ABCG2
levels and higher plasma concentrations of erlotinib in a
prospective clinical study of 80 patients with non-small-cell
lung cancer, head and neck cancer, and ovarian cancer [263].
ABCG2 expression is increased in topotecan resistant
ovarian cancer cells [264,265]. ABCG2 is induced by physiological concentrations of oestrogen in the PA-1 ovarian
cancer cell line transfected to overexpress oestrogen receptor suggesting the possibility that estrogens can directly
stimulate the production of this multidrug resistance protein [266]. Our own recent immunohistochemistry studies
detected minimal ABCG2 protein in ovarian cancer tissues
prior to chemotherapy (Fig. 4A and B) but found increased
membranous ABCG2 levels in tumour tissues from patients
with recurrent ovarian cancers that had received combined
carboplatin + paclitaxel treatment (Fig. 4E and F).
2.7.3. ABCG4
The function of ABCG4 in humans is unknown, but mouse
experiments suggest it transports oxysterols in the brain
[267]. Very little is known about any possible function in
cancer, but it has been shown to be highly expressed in nonsmall-cell lung cancer and correlate with grade and stage
[268]. ABCG4 was found to be hypermethylated before and
after decitabine treatment in ovarian cancer patients with
longer survival [75]. Further studies are required to understand it role in ovarian cancer.
2.7.4. ABCG5 and ABCG8
The ABCG5 and ABCG8 proteins unite to form the
functional heterodimeric transporter [269] and are involved
in the secretion of plant sterols and cholesterol into the bile in
the liver. Mutations in either ABCG5 or ABCG8 cause sitosterolemia, a rare autosomal recessive disorder characterised
by accumulation of both plant-derived sterols and animalderived sterol (cholesterol) in plasma and tissues, leading
to the development of xanthomas [270]. Whilst most of the
attention has been directed at liver and gall bladder diseases,
ABCG5 and ABCG8 were also found to be significantly
down-regulated in breast cancer [52] and overexpressed in
gastric cancer [271]. Additionally, ABCG5 was associated
with poor outcome in node-negative colorectal cancer [272]
and linked with chemoresistance of head and neck cancers
[273]. No studies to date have investigated whether altered
sterol/cholesterol transport by ABCG5/8 plays a role in
ovarian cancer. This heterodimer warrants further study, as

early studies show that cholesterol availability in ovarian
cancer cells may play a role in their chemoresistance [274].
3. Cancer stem cells and ABC transporters

Ovarian tumour initiating cancer cells and SP cells with
stem cell-like properties have been shown to overexpress several ABC drug transporters including ABCB1 and ABCG2
[275277]. Chemoresistance in SP cells is mediated by both
ABCB1 and ABCG2 [260,275,278280]. When injected i.p.
into nude mice, SP cells were more tumorigenic than nonSP cells [275]. Ovarian cancer stem cells characterised by
CD44+ CD117+ isolated from SKOV3 cells when grown in
3D culture where reported to be more resistant to anti-cancer
drugs and had increased ABCG2 and ABCB1 expression
[281]. A study by Bourguignon and colleagues showed that
activation of the stem cell marker Nanog was mediated by
ABCB1 via hyaluronan-CD44 interactions [282]. A more
recent study demonstrated that chemoresistance in ovarian
tumour-initiating cells is mediated by c-Kit and involves the
activation of ABCG2 [283]. Other ABC transporters shown
to be up-regulated in cancer stem cells are ABCA3, ABCA5
and ABCB5. ABCA3 is up-regulated in AML SP and SP
cells isolated from neuroblastomas [284,285] and ABCA5
has been identified in osteosarcoma stem cells [64]. ABCB5
is increased in cancer stem cells identified in melanoma [286]
and squamous cell carcinomas [152].
4. Clinical trials using inhibitors of ABC transporters

Although ABC transporter inhibitors have been very
effective in preclinical studies [287289] (Table 1), clinical trials involving a range of ABC transport inhibitors have
proven disappointing [29,289291]. Historically, research on
blocking ABC transporter mediated MDR has focused on
inhibiting the activity of the transporters. In the 1980s Verapamil was discovered, the first drug to inhibit ABCB1s role
in decreasing sensitivity to vincristine and vinblastine [292].
Then came the discovery that cyclosporine A (CsA) could
reverse primary resistance of leukaemia and ascites carcinoma cells to vincristine and daunorubicin [293,294]. Both
of these drugs work by interacting with the substrate binding
pocket of ABCB1 [295,296] but failed in drug trials because
of immunosuppressive and nephrotoxic effects [297].
First generation ABCB1 inhibitors nicardipine and
nifedipine which also inhibit ABCB1 efflux were similarly
found to be quite toxic when given at high doses required to
inhibit ABCB1. The second generation inhibitors included
an analogue of cyclosporine A (CsA), PSC 833 or valspodar,
which was 10 fold more potent than CsA, but did not elicit
the toxicity or immunosuppressive response of CsA [298]. A
phase I/II trial where valspodar was given to ovarian cancer
patients who had failed platinum- and anthracycline-based
chemotherapy showed some promise of acceptable toxicity

and efficacy [299]. Among the 33 patients treated at the
maximal tolerated dose for doxorubicin, one (3%) had a
complete response, four (12%) had a partial response and an
additional seven patients (21%) experienced a stabilization
of their previously progressive disease. Another phase I
study treating patients with advanced breast and ovarian
cancer with pegylated liposomal doxorubicin and valsopdar
also did not report increased toxicity [300]. Some clinical
benefit was observed in 5 out of 10 patients with advanced
ovarian cancer receiving a combination of paclitaxel and
valspodar [301]. However a phase II trial with patients with
refractory ovarian cancer found that valspodar was ineffective at reversing paclitaxel resistance [302]. Valspodar failed
to enhance efficacy of paclitaxel and carboplatin treatment
and was more toxic in a phase III trial with advanced
ovarian cancer patients [303]. Similarly, dexverapamil, a
dextrorotatory isomer of verapamil never progressed beyond
phase II clinical trials for a range of cancers in the 90s (but
not ovarian cancer) despite data suggesting tolerable toxicity
and some level of efficacy [304,305]. Similarly, another
second generation inhibitor, biricodar, known to inhibit
efflux activity of ABCB1 as well as ABCC1 and ABCG2,
showed some efficacy in a phase II trial in ovarian cancer
patients [306] but did not have sufficient efficacy to progress
to phase III for ovarian cancer or other malignancies [307].
A wide range of third generation ABCB1 inhibitors have
also been evaluated in clinical trials. Tariquidar which inhibits
ABCB1 by binding at a site distinct from the paclitaxel and
vinblastine recognition site [308] provided enhanced sensitivity to doxorubicin, paclitaxel, etoposide, and vincristine
in phase III trials with lung cancer patients. However, trials had to be terminated due to its increased toxicity and
interaction with the chemotherapeutics. A trial investigating
the efficacy of tariquidar in addition to docetaxel in ovarian cancer patients showed a partial response in a single
patient after 5 failed lines of chemotherapy [309]. The results
were similar for other third generation ABCB1 inhibitors
such as zosuquidar, elacradir, and dofequidar. Zosuquidar
(LY335979), a difluorocyclopropyl quinoline, which binds
with high affinity to ABCB1 did not result in pharmacokinetic interactions with co-administered doxorubicin [310].
In a phase I trial of 36 patients with resistant cancers treated
with zosuquidar and docetaxel, 14 patients had disease stabilization and one patient with ovarian carcinoma, previously
treated with paclitaxel before the study had a partial response
with the combined treatment [311]. However, zosuquidar
did not provide any additional survival benefit for breast
cancer patients with metastatic or locally recurrent breast
cancer who received prior chemotherapy [312]. Elacridar
(GF-120918) which inhibits the activity of both ABCB1 and
ABCG2 was shown to increase the oral bioavailability of
topotecan but was not further investigated in phase II/III clinical trials [313,314]. Dofequidar (MS209) can be given in
combination with docetaxel, with limited effect on docetaxel
toxicity or pharmacokinetics [315]. Although dofequidar plus
239
cyclophosphamide, doxorubicin, and fluorouracil (CAF)

therapy in comparison with CAF alone was well tolerated
in patients with advanced or recurrent breast cancer it only
had limited efficacy in patients who had not received prior
therapy [316].
Recently, two new ABCB1 inhibitors have been identified
by screening small molecule compounds together with paclitaxel against resistant ovarian cancer cells lines. NSC23925
which was synthesized in the 1940s as an anti-malarial drug,
inhibits ABCB1 and increases accumulation of paclitaxel
but does not inhibit ABCC1 or ABCG2-mediated MDR.
Its inhibitory effect was not altered by co-incubation with
the ABCB1 inhibitor verapamil, suggesting that NSC23925
itself is not a substrate of ABCB1 [317]. In follow up
studies, NSC23925 completely reversed paclitaxel resistance in SKOV-3TR ovarian MDR mouse xenograft models,
without increasing the level of paclitaxel toxicity [318].
Similarly, NSC77037 reversed ABCB1 MDR without reversing ABCC1 or ABCG2-mediated MDR [319]. The ABCC1
inhibitor reversan has recently being identified by screening
small molecule libraries [320]. Reversan which can inhibit
the function of both ABCC1 and ABCB1 was found to be
non-toxic in murine models of neuroblastoma [320] but has
yet to be tested in patients.
Tryosine kinase inhibitors erotinib, getitinib, and imatinib increase the accumulation and cytotoxicity of ABCG2
substrates, mitoxantrone and methotrexate [321] and also
inhibit expression of ABCG2 via the P13K-AKT pathway
[322]. Lapatinib, a small pan-erbB inhibitor which can block
ABCB1 and ABCG2 efflux of toptecan, failed to show sufficient efficacy in refractory ovarian cancer patients to progress
to phase III trials [323]. Athough imatinib treatment was well
tolerated it did not produce clinical responses in patients
with recurrent ovarian cancer either alone [324,325] or in
combination with docetaxel [326].
Other agents including the non-steroidal antiinflammatory drug sulindac and the src inhibitor saracatinib
(AZD0530) shown to inhibit ABC transporter activity have
also been evaluated in clinical trials. A Phase I clinical
trial found that the combination of epirubicin with sulindac
was well tolerated in patients with advanced cancer [327].
Recent studies have shown that sulindac can inhibit ovarian
cancer cell proliferation and reduce tumour growth in mice
[328]. Sulindac is being studied in clinical trials for colon
cancer [329], however, no studies have been reported to
date in patients with refractory ovarian cancer. Saracatinib
which was shown to inhibit ABCB1 function and enhance
the effect of paclitaxel in ABCB1 overexpressing cancer
cells [330] has just completed a Phase II trial in patients
with relapsed platinum-resistant ovarian cancer [331]. The
phosohodiesterase-5 inhibitor sildenafil, has also been
shown to inhibit both ABCB1 and ABCG2 at clinical
achievable concentrations and efflux several chemotherapy
drugs including paclitaxel [332]. In animal models sildenafil
improved the efficacy of doxorubicin against prostate cancer
[333]. However no clinical trials have been reported to date
240
examining the effect of phosohodiesterase-5 inhibitors on

ABC transporters. The anti-viral drug and protease inhibitor
ritonavir has also been shown to be a potent ABCB1
inhibitor [334]. In combination with docetaxel, ritonavir was
well tolerated and increased the bioavailability of docetaxel
[335].
A major reason for the failure of three generations of
ABC inhibitors has been the unexpected alterations in the
pharmacokinetics of chemotherapy drugs and increased toxicity when combined with ABC transporters inhibitors. This
is likely due to the fact that the physiological function of
many ABC transporters is to provide protection against toxins. Thus inhibiting ABC transporters is likely also to inhibit
their ability to reduce the toxicity of chemotherapy drugs.
Furthermore ABC transporters are involved in the absorption,
excretion and distribution of chemotherapy agents. Many
inhibitors may yet be proven to be effective treatments if
they can be delivered with greater specificity to the cancer cells and increase the bioavailability of the drug only
in the area of the tumour. In addition to these issues, many
clinical trials were initiated without adequate preclinical evaluation. Increased accumulation of chemotherapy agents in
cell lines expressing a single ABC transporter fail to take
into consideration the physiological functions of the transporters in a whole organism, and the possible co-expression
of many transporters within tumours and neighbouring tissues. Analysis of the structures of ABCB1 in the presence
of several substrates including paclitaxel and doxorubicin
have shown a large degree of flexibility in the transporter
cavity when it comes to substrate interaction, highlighting
the difficulty of designing competitive inhibitors [336338].
Additionally, many ABC transporter inhibitors exhibit crossinhibition with other necessary proteins, leading to increased
side effects. Thus all new ABC transporter inhibitors need
to be tested in preclinical animal models with established
tumours. There is also much speculation as to the best animal models to use for ovarian cancer as they do not model all
subtypes and are not truly reflective of human disease [29]. In
addition to this, most clinical trials did not specifically target
patients with particular cancer type, with many assessing the
effects on tumours from a range of origins. Another potential
reason for the failure of the ABC transporter inhibitor trials
is that most patients in the clinical studies were enrolled after
multiple lines of therapy, and often differing therapies, making it difficult to assess their current chemoresistant states.
Furthermore, none of the trials selected patients based on the
expression levels of the ABC transporters, thereby allowing
effects seen in patients with high ABC transporter expression to be potentially masked by patients not expressing the
inhibitors intended target at all. And probably most importantly, most clinical trials to date have only targeted ABCB1
and more recently ABCC1 and ABCG2. This is a major flaw,
as Table 1 shows, many ABC transporters are capable of
effluxing chemotherapy agents than most would generally be
aware and this number is increasing each year. Single ABC
transporter inhibitors fail to take this into account, and any
effects of the inhibitor may well be masked by other ABC

transporters still left in play. Future clinical trials should take
these many factors into account to ensure the best outcome.
5. Alternative strategies to overcome ovarian cancer

MDR
The use of monoclonal antibodies, siRNAs, antisense
oligonucleotides and transcription factor regulators are alternative approaches to target ABC transporters [289,291].
Double stranded antisense oligonucleotides were effective
at inhibiting ABCB1 expression in A2780/Adr ovarian cancer cell lines [339]. Several studies have shown that RNAi
methods are effective at reversing chemotherapy resistance in
ovarian cancer cells in vitro and in vivo studies [82,340,341].
ABCC2 siRNA were also shown to be effective at inhibiting
ABCC2 expression and reversing resistance against cisplatin and paclitaxel of the human ovarian carcinoma cell
line A2780RCIS [342]. Treatment with DNA G-quadruplex
oligonucleotides decreased expression of ABCB1 in SKOV3 cells and reversed their resistance to paclitaxel [343].
Although promising, none these approaches have made it into
clinical trials yet. A major challenge of using RNAi mediated
methods is to specifically deliver them to resistant tumour
cells and avoid systemic side effects.
Another area under current investigation is the use of ABC
transporter inhibitors to block the bodys natural ability to
efflux and remove drugs administered orally, which show
reduced efficacy in comparison to intravenous administration. In particular, the ABCB1 inhibitor, HM30181 could
increase the bioavailability of paclitaxel in rats and inhibited
the growth of colon tumour xenografts with greater efficacy
when given orally instead of intravenously [344]. Follow up
phase I trials have shown that HM30181 is well tolerated
by patients [345,346]. Phase Ib trials are now recruiting to
test OraxolTM , a new oral formulation consisting of paclitaxel and HM30181 in a range of cancer patients including
ovarian cancer [347].
Many natural products have also shown some promise
in reversing ABC transporter mediated chemoresistance in
ovarian cancer cells. Several compounds including curcumin
and plant polyphenols demonstrated broad spectrum effects
on more than one ABC drug transporter [348355]. The
major components of green tea, epigallocatechin gallate, and
cruciferous vegetables, sulforaphane respectively were effective at overcoming paclitaxel resistance in SKOV3TR-ip2
xenografts by inducing apoptosis [356]. However a recent
phase trial II found that epigallocatechin gallate enriched
green tea did not improve recurrence rates in women with
advanced ovarian cancer after completing 68 cycles of first
line chemotherapy [357]. A recent study found that Brucea
javanica fruit oil emulsion in conjunction with cisplatin treatment led to smaller tumour in SKOV-3 xenograft mice and
downregulation of ABCC1 [358]. Natural products have great
potential for treating refractory disease in cancer patients;
however unpredictable pharmacokinetic drug interactions

with chemotherapeutics and toxicity will need to be carefully
evaluated.
Alternative drug delivery approaches using liposomes and
nanoparticles have also been tested in vitro and in vivo
ovarian cancer models. Liposomes containing tariquidar and
paclitaxel resulted in greater toxicity to the drug resistant ovarian cancer SKOV-3TR [359,360]. Biodegradable
polymeric nanoparticle formulations combining ABCB1
siRNA and paclitaxel could increase cytotoxicity in MDR
SKOV3(TR) cells by increasing cellular levels of paclitaxel
[361]. Chitosan shRNA ABCB1 plasmid nanoparticles were
also effective at reversing paclitaxel resistance of A2780/TS
ovarian cancer cells [362]. Nanoscale coordination polymers
containing cisplatin and ABCB1 siRNA reduced the growth
of cisplatin resistant SKOV-3 xenografts in mice [363].
CD44 targeted HA-PEI/HA-PEG/ABCB1 siRNA nanoparticles caused decreased tumour growth after treatment with
paclitaxel in taxane resistant SKOV-3 and OVCAR-8 cells
[364,365]. Nanoparticle technology holds great promise for
targeted delivery of specific ABC inhibitors in combination
with chemotherapy drugs and deserves further attention.
Studies have shown that as cancer cells become more
resistant to one drug, they can simultaneously become more
susceptible to another, an event termed collateral sensitivity [366368]. In particular, common ovarian cancer drugs,
taxanes and platinum based agents, showed an inverse
relationship in resistance [369]. This concept has been extensively reviewed in [370]. A greater understanding of how
this occurs may lead to future therapies that can manipulate
collateral sensitivity to established drugs.
Another approach is to utilize compounds which lead
to a reduction in ABC transporter expression. One such
compound is NSC73306 which causes a loss of ABCB1
expression in vitro as well as a reduced MDR phenotype
[371,372]. NSC73306 exhibited selective toxicity to ABCB1
expressing MDR cancer cells by reducing expression of
ABCB1 rather than suppressing ABCB1 function [371]. An
additional 15 ABCB1 selective inhibitors were identified
by screening the National Cancer Institutes Developmental
Therapeutics Program drug repository [373]. These compounds along with NSC73306 and TSC Dp44mT [374] which
exploit ABCB1 expression rather ABCB1 function to induce
cytotoxicity have great potential to treat ABCB1 mediated
MDR. However to date there have been limited pre clinical
studies in mice and none of these have been tested in clinical
trials to date.
Antibodies are another exciting avenue being explored to
reverse ABC transporter mediated MDR. Antibodies against
ABCB1 have been shown to promote both lymphocyte- and
monocyte-mediated tumour cell killing [375]. Immunisation
against the extracellular loops of the mouse homologue of
ABCB1 doubled the survival time of xenograft mice [376].
Mouse monoclonal ABCB1 antibody UIC2 was shown to
inhibit the in vitro efflux of drug substrates but required
a substrate-bound form of ABCB1 in order to bind almost
241
100% of surface ABCB1 [377,378]. It was recently shown

that treatment with the UIC2 antibody as well as doxorubicin
dramatically reduced the size of epidermoid carcinomas in
SCID mice [379]. HPMA copolymers containing chemotherapy agents have used UIC2 as a way to target ABCB1
expressing ovarian cancer cells and showed a drastically
reduced IC50 for both chemotherapy agents tested [380]. An
ABCB1 antibody has also been conjugated to lentivirus as
a way to target gene therapy delivery [381]. These study
shows that there may be a way to specifically target cells
over-expressing ABC transporters, overcoming the problems
of toxicity via inhibition of physiological function in normal
tissues.
6. Conclusion
It has become increasingly apparent that many ABC transporters and not just ABCB1 play important roles in MDR
with 20 ABC transporters now known to efflux chemotherapy
drugs. ABC transporters contribute to tumour biology independently of their ability to efflux cytotoxic drugs and are also
involved in lipid export and lipid homeostasis and mediate the
release of bioactive lipids that activate signalling cascades
involved in cell proliferation, migration and tumorigenesis
[290]. Furthermore, ABC transporters also have important
roles in drug distribution and drug access across blood brain
barrier and intestine [382]. Unfortunately clinical trials evaluating three generations of ABC inhibitors have failed. A lot
has been learned from the experience and many reasons for
the failure have been realised. A major reason has been the
unexpected alterations in the pharmacokinetics of chemotherapy drugs and increased toxicity when combined with ABC
transporters inhibitors. One reason for these outcomes may
be the method of inhibition. As many of the ABC transporters
commonly targeted serve important physiological functions,
blocking this function results in the side effects outweighing any effect on chemoresistance. One way around this
issue in the future would be to have inhibitors designed to
block the recognition sites of the chemotherapy drugs, whilst
allowing the ABC transporter to perform its physiological
function. One of the best ways to achieve this would be to
structurally design inhibitors for the drug recognition sites.
However, this is not as easily done as said, as only a handful of ABC transporter structures have been determined to
date [3137], and most recently, human ABCB10 [38] and
mouse ABCB1 in the presence of designed substrates [39].
This is due to the difficulties in expressing, purifying, and
crystallizing the proteins in their native conformation in cellular membranes. It is our belief, that once structures become
more readily accessible, including structures of the transporters interacting with chemotherapeutic and physiological
substrates, that ABC inhibitors will prove a valid and effective way to reduce chemoresistance. Furthermore, improved
models are needed to improve pre-clinical selection if we
want to see more success in future clinical trials.
242
This review has revealed that there is more to the MDR

phenomenon than the most commonly studied ABC transporters, including ABCB1, ABCC1, and ABCG2. Indeed,
a thorough review of the literature has identified at least
20 ABC transporters that are capable of effluxing a range
of chemotherapy drugs (Table 1). As many transporters and
drugs have never been tested, it is extremely likely that this
number will continue to rise. It has become apparent that a
large number of ABC transporters could well be contributing to the MDR but have been neglected in favour of their
more popular cousins. The advancements in technology in
the omics fields provide researchers with the opportunity to
investigate the changes in cancer cells of not one or a few,
but all the ABC transporters in response to chemotherapy
drugs and new inhibitors. It is likely that multiple agents
will need to be combined to inhibit a wider range of ABC
transporters to prove effective at combating chemoresistance.
ABC transporter inhibition still remains an attractive potential adjuvant to chemotherapy but the discovery of novel
nontoxic inhibitors and the development of more effective
targeted therapies will be required to impact clinical outcome.
The most effective therapies will be those that find a way to
target not only multiple transporters at once, but also only
target cancer cells, avoiding toxicity effects from inhibiting
the physiological functions of the ABC transporters.
Conict of interest
The authors have no conflict of interest to declare.
Acknowledgements
This research has been funded by the Ovarian Cancer
Research Foundation (OCRF), Australia, Royal Adelaide
Hospital Clinical Research Fund, Cancer Council of South
Australia & South Australian Health and Medical Research
Institute.
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Biographies
Miranda P. Ween, PhD received her PhD in 2010 at the
University of Adelaide (Australia) with her thesis dedicated
to understanding the role of extracellular matrix in ovarian
cancer progression. Her focus then changed to the role of
ABC transporters in chemoresistance, before moving to the
Research Centre for Infectious Diseases at the University of
Adelaide to study ABC transporters, and most recently to
SA Pathology to investigate the role of metals in diseases
affecting the lung.
256
Mark Armstrong received his MRes in 2013 at the University of Exeter (United Kingdom) with his thesis dedicated to
using a transcriptomics approach for identifying possible cancer biomarkers in gastric tissue samples. He now works for
the Data Management and Analysis Centre at the University
of Adelaide (Australia).
Martin K. Oehler, MD PhD FRANZCOG CGO is
the Director of Gynaecological Oncology, Royal Adelaide Hospital and Group Leader for Reproductive Cancer
Research, School of Paediatrics and Reproductive Health,
Robinson Research Institute, University of Adelaide and
investigates on topics related to gynaecological oncology, early detection of ovarian cancer and mechanisms of
chemoresistance.
Carmela Ricciardelli, PhD is cancer cell biologist
and Group leader for Reproductive Cancer Research,
School of Paediatrics and Reproductive Health, Robinson
Research Institute, University of Adelaide. Her research
focuses on the understanding the cross-talk between cancer cells and the tumour microenvironment, early detection
of ovarian cancer and mechanisms of metastasis and
chemoresistance.

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Critical Reviews in Oncology/Hematology 96 (2015) 220256

The role of ABC transporters in ovarian cancer progression and

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

2.3.6. ABCC6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

that have inherent resistance to drugs and are capable of

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

Cancer drug substrates

Glibenclamide/Glyburide [383], JNJ-26854165 [384]

Mitoxantrone [385], Estramustine [385], Methotrexate [54]

MS-209 [393], MK-571[393]1, Ochratoxin A [393],

Daunorubicin [443], Digoxin [443], Paclitaxel [443], Vinblastine

Cyclosporin A [443], Valspodar/PSC833 [443], Verapamil

5-Fluorouracil [394], Camptothecin [394], Doxorubicin [286],

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

Cancer drug substrates

Cyclosporin A [175], Valspodar/PSC833 [175], Verapamil

Chlorambucil [444], Daunorubicin [445], Doxorubicin [445],

Agosterol A [409], Annamycin [451], Antimalarials [452],

Antimalarials [452], MK571 [471], PCS833 [471],

MK571 [471], Polyphenols [349], Sildenafil [473],

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

Cancer drug substrates

5-Fluorouracil [483], Fasudil [484]

Bisantrene [485], Dasatinib [397], Doxorubicin [486],

Apatinib [414], Curcumin [353], Curcumin [352],

to be up-regulated in some leukemias and breast cancer

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

high ABCA4 expression was associated with chemotherapy

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

Further studies will determine whether ABCA5 is involved

DNA hypomethylating agent (decitabine) in ovarian cancer

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

Pre-treatment advanced stage (n = 5)

ABCB1 expressed in 40% of cases

Immunohistochemistry (frozen sections

ABCB1 expression observed in 7% of cases and [86]

Immunohistochemistry (paraffin, microwave retrieval) ABCB1 expressed in 13% cases. ABCB1

ABCB1 expressed in 27.6% of cases. No

Immunohistochemistry (frozen) JSB-1 monoclonal

ABCB1 expressed in 17.4% cases

ABCB1 expressed in 96% cases

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

Immunohistochemistry (paraffin, microwave

ABCB1 expressed in 12.9% cases

Immunohistochemistry (paraffin, microwave

Pre-treatment serous (n = 60)

Pre-treatment (n = 43) and post

Immunohistochemistry (paraffin, microwave

ABCB1 expression in 98% of cases. High

Immunohistochemistry (paraffin, microwave

ABCB1 expressed in 92.8% of cases

ABCB1 expressed in 20% of cases using both

ABCB1 expressed in 85.9% cases

Immunohistochemistry (paraffin, microwave

ABCB1 expressed in 80% of cases. High

ABCB1 expressed in 57.5% of cases. High

ABCB1 expression associated with PFS

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

2.2.2. ABCB2 and ABCB3

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256

cells [60], providing evidence that ABCB4 may play a similar

[155], and colon cancer [156]. c-MYC was shown to bind to

M.P. Ween et al. / Critical Reviews in Oncology/Hematology 96 (2015) 220256