Ion channels and transporters in the development of drug resistance in cancer cells

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Abstract

Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of ion transporters is the main focus of this paper and we demonstrate how pro-apoptotic ion channels are downregulated, while anti-apoptotic ion transporters are upregulated in MDR. We also discuss whether upregulation of ion transport proteins that are important for proliferation contribute to MDR. Finally, we discuss the possibility that the development of MDR involves sequential and localized upregulation of ion channels involved in proliferation and migration and a concomitant global and persistent downregulation of ion channels involved in apoptosis.

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Most cited references 78

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Membrane transporters in drug development.

Kathleen M. Giacomini, Shiew-Mei Huang, Donald Tweedie … (2010)

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

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Drug resistance and the solid tumor microenvironment.

Olivier Trédan, Carlos M. Galmarini, Krupa Patel … (2007)

Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.

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Physiology of cell volume regulation in vertebrates.

Else K. Hoffmann, Ian H. Lambert, Stine F. Pedersen (2009)

The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adaptive (e.g., altered expression of osmolyte transporters and heat shock proteins) measures and, in most cases, activation of volume regulatory osmolyte transport. After acute swelling, cell volume is regulated by the process of regulatory volume decrease (RVD), which involves the activation of KCl cotransport and of channels mediating K(+), Cl(-), and taurine efflux. Conversely, after acute shrinkage, cell volume is regulated by the process of regulatory volume increase (RVI), which is mediated primarily by Na(+)/H(+) exchange, Na(+)-K(+)-2Cl(-) cotransport, and Na(+) channels. Here, we review in detail the current knowledge regarding the molecular identity of these transport pathways and their regulation by, e.g., membrane deformation, ionic strength, Ca(2+), protein kinases and phosphatases, cytoskeletal elements, GTP binding proteins, lipid mediators, and reactive oxygen species, upon changes in cell volume. We also discuss the nature of the upstream elements in volume sensing in vertebrate organisms. Importantly, cell volume impacts on a wide array of physiological processes, including transepithelial transport; cell migration, proliferation, and death; and changes in cell volume function as specific signals regulating these processes. A discussion of this issue concludes the review.

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Journal

Journal ID (nlm-ta): Philos Trans R Soc Lond B Biol Sci

Journal ID (iso-abbrev): Philos. Trans. R. Soc. Lond., B, Biol. Sci

Journal ID (publisher-id): RSTB

Journal ID (hwp): royptb

Title: Philosophical Transactions of the Royal Society B: Biological Sciences

Publisher: The Royal Society

ISSN (Print): 0962-8436

ISSN (Electronic): 1471-2970

Publication date (Print): 19 March 2014

Publication date PMC-release: 19 March 2014

Volume: 369

Issue: 1638 , Theme Issue ‘Ion channels, transporters and cancer’ compiled and edited by Mustafa B. A. Djamgoz, R. Charles Coombes and Albrecht Schwab

Electronic Location Identifier: 20130109

Affiliations

Department of Biology, University of Copenhagen , 13 Universitetsparken, Copenhagen Ø 2100, Denmark

Author notes

e-mail: ekhoffmann@ 123456bio.ku.dk

One contribution of 17 to a Theme Issue ‘ Ion channels, transporters and cancer’.

Article

Publisher ID: rstb20130109

DOI: 10.1098/rstb.2013.0109

PMC ID: 3917363

PubMed ID: 24493757

SO-VID: c4ebc595-6e11-435f-9792-2c635a7176cf

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© 2014 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited.

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cover-date March 19, 2014

ScienceOpen disciplines: Philosophy of science

Keywords: cancer,drug resistance,tumour proliferation,apoptosis,ion channels in cancer

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ScienceOpen disciplines: Philosophy of science

Keywords: cancer, drug resistance, tumour proliferation, apoptosis, ion channels in cancer

Ion channels and transporters in the development of drug resistance in cancer cells

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Abstract

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Karger: Oncology

Most cited references 78

Membrane transporters in drug development.

Drug resistance and the solid tumor microenvironment.

Physiology of cell volume regulation in vertebrates.

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