Role of ABC transporters in cancer chemotherapy

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Abstract

Multidrug resistance (MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality. The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette (ABC) transporters, which can increase efflux of drugs from cancer cells, thereby decreasing intracellular drug concentration. Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs. This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR.

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Most cited references 72

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Network modeling links breast cancer susceptibility and centrosome dysfunction.

Miguel Pujana, Jing-Dong J. Han, Lea M. Starita … (2007)

Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.

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Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview.

Alfred Schinkel, Johan Jonker (2003)

Active drug efflux transporters of the ATP binding cassette (ABC)-containing family of proteins have a major impact on the pharmacological behavior of most of the drugs in use today. Pharmacological properties affected by ABC transporters include the oral bioavailability, hepatobiliary, direct intestinal, and urinary excretion of drugs and drug-metabolites and -conjugates. Moreover, the penetration of drugs into a range of important pharmacological sanctuaries, such as brain, testis, and fetus, and the penetration into specific cell- and tissue compartments can be extensively limited by ABC transporters. These interactions with ABC transporters determine to a large extent the clinical usefulness, side effects and toxicity risks of drugs. Many other xenotoxins, (pre-)carcinogens and endogenous compounds are also influenced by the ABC transporters, with corresponding consequences for the well-being of the individual. We aim to provide an overview of properties of the mammalian ABC transporters known to mediate significant transport of clinically relevant drugs.

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Human ATP-binding cassette (ABC) transporter family

Vasilis Vasiliou, Konstandinos Vasiliou, Daniel Nebert (2009)

There exist four fundamentally different classes of membrane-bound transport proteins: ion channels; transporters; aquaporins; and ATP-powered pumps. ATP-binding cassette (ABC) transporters are an example of ATP-dependent pumps. ABC transporters are ubiquitous membrane-bound proteins, present in all prokaryotes, as well as plants, fungi, yeast and animals. These pumps can move substrates in (influx) or out (efflux) of cells. In mammals, ABC transporters are expressed predominantly in the liver, intestine, blood-brain barrier, blood-testis barrier, placenta and kidney. ABC proteins transport a number of endogenous substrates, including inorganic anions, metal ions, peptides, amino acids, sugars and a large number of hydrophobic compounds and metabolites across the plasma membrane, and also across intracellular membranes. The human genome contains 49 ABC genes, arranged in eight subfamilies and named via divergent evolution. That ABC genes are important is underscored by the fact that mutations in at least I I of these genes are already known to cause severe inherited diseases (eg cystic fibrosis and X-linked adrenoleukodystrophy [X-ALD]). ABC transporters also participate in the movement of most drugs and their metabolites across cell surface and cellular organelle membranes; thus, defects in these genes can be important in terms of cancer therapy, pharmacokinetics and innumerable pharmacogenetic disorders.

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Author and article information

Journal

Journal ID (nlm-ta): Chin J Cancer

Journal ID (iso-abbrev): Chin J Cancer

Journal ID (publisher-id): CJC

Title: Chinese Journal of Cancer

Publisher: Sun Yat-sen University Cancer Center

ISSN (Print): 1000-467X

ISSN (Electronic): 1944-446X

Publication date (Print): February 2012

Volume: 31

Issue: 2

Pages: 51-57

Affiliations

[1 ]Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professionals, St. John's University, Jamaica, NY 11439, USA;

[2 ]State Key Laboratory of Oncology in South China;

[3 ]Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 51006, P. R. China.

Author notes

Corresponding Author: Zhe-Sheng Chen, Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professionals, St. John's University, Jamaica, NY 11439, USA Tel: +1-718-990-1432; Email: chenz@ 123456stjohns.edu .

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Publisher ID: cjc-31-02-051

DOI: 10.5732/cjc.011.10466

PMC ID: 3777472

PubMed ID: 22257384

SO-VID: 5364a366-11b1-4423-86ff-49285bc33880

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License, which allows readers to alter, transform, or build upon the article and then distribute the resulting work under the same or similar license to this one. The work must be attributed back to the original author and commercial use is not permitted without specific permission.

Role of ABC transporters in cancer chemotherapy

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Cancer Metabolism

Most cited references 72

Network modeling links breast cancer susceptibility and centrosome dysfunction.

Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview.

Human ATP-binding cassette (ABC) transporter family

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