Mini-reviewMembrane transporters and channels in chemoresistance and -sensitivity of tumor cells
Introduction
Membrane transporters and ion channels are encoded by numerous gene families, comprising ∼4% of genes in the human genome, with 406 genes encoding ion channels and 883 encoding a broad variety of transporters, of which 350 were classified as intracellular transporters [1]. Many of these proteins play key roles in pharmacology, affecting entry and extrusion of drugs into and out of cells. In particular, ATP-binding cassette (ABC) transporters, such as the multiple drug resistance transporter MDR1 (multidrug resistance 1, ABCB1 or P-glycoprotein), mediate energy-dependent drug efflux and play a main role in chemoresistance [2].
Multiple types of membrane transporters contribute to chemosensitivity and -resistance of tumor cells. Water-soluble drugs, such as cisplatin, nucleoside analogues and antifolates, cannot cross the plasma membrane unless they ‘piggy-back’ onto membrane transporters, or enter through hydrophilic channels in the membrane. Resistance may result from decreased activity of the uptake transporters, or alternatively, enhanced efflux. For hydrophobic drugs, such as the natural products vinblastine, doxorubicin, and paclitaxel, entry occurs largely by diffusion across the membrane, although this process can also be critically enhanced by transport proteins. Cellular resistance to these drugs commonly results from increased drug efflux mediated by energy-dependent transporters. In addition to the direct relationship between transporters and drug substrates, indirect mechanisms may also modulate chemosensitivity. For example, transporters and channels can affect chemosensitivity by providing nutrients to cancer cells or modulating the electrochemical gradient across membranes, thereby, modifying apoptosis pathways or the efficiency of drug diffusion along electrochemical gradients into cells.
Transporters can be classified into passive and active transporters. The latter are further classified as primary- or secondary-active transporters according to the mechanism of energy coupling. The ABC (ATP binding cassette) transporters are primary active transporters, driven by energy released from ATP by inherent ATPase activity, exporting substrates from the cell against a chemical gradient—the basis of broad chemoresistance. Ion pumps, also acting as ATPases, generate electrochemical ion gradients across membranes, which in turn drives secondary-active transporters to translocate co-substrates against concentration gradients. The majority of passive transporters (or facilitated transporters allowing substrates to equilibrate along concentration gradients), secondary-active transporters, and exchangers belong to solute carriers (SLCs) families. This review summarizes the role of membrane transporters and ion and water channels, in determining chemosensitivity. Understanding their functions in tumor cells may prove useful in predicting anticancer drug response, and offers the potential for the selection of optimal treatment regimens for individual patients. In addition, transporters could serve as potential therapeutic targets to overcome drug resistance.
Section snippets
ABC transporters and chemoresistance
The association between ABC transporters and cancer drug resistance has been known for over 25 years. To date, 49 different ABC transporter genes, grouped into seven subfamilies (from A to G) based on sequence homology, have been identified in the human genome (ABC transporter web page: http://nutrigene.4t.com/humanabc.htm). ABC transporters are responsible for transport of diverse substrates through membranes against a concentration gradient, with ATP hydrolysis providing the driving force.
SLC transporters and chemosensitivity
To date ∼300 SLC genes have been cloned and grouped into 43 families [36] (http://www.bioparadigms.org/slc/). Each family of SLC carriers transports specific substrates, such as amino acids, oligopeptides, sugars, monocarboxylic acid, organic cations, anions, phosphates, nucleosides, metals and water-soluble vitamins, SLCs typically mediate uptake and chemosensitivity for hydrophilic drugs. Structurally, these drugs often resemble the natural substrates of the respective transporters. In some
Ion pumps in chemosensitivity/resistance
Ion pumps (ATPases) are active, ATP-dependent ion transporters that pump ions such as Na+, K+, H+, Ca2+ and Cu2+ out of cells or into organelles [36]. They generate and maintain electrochemical ion gradients across the membrane. The ion gradients are associated with accumulation, intracellular distribution, and sensitivity to anticancer drugs [71]. Such ion gradients are also used by secondary-active, ion-coupled SLC transporters to drive uphill transport of nutrients, ions and drugs. In
Ion and water channels and roles in apoptosis
Ion channels span the cell membrane, forming a conduction pathway, or pore, allowing the movement of ions down their electrochemical gradient across the membrane. Solute transport by channels is typically much faster than that by transporters since translocation does not require a conformational change, but rather, permits select solutes to flow freely along their electrochemical gradient. Ion channels modulate electrochemical gradients generated by ion pumps and ion exchangers. Maintenance of
Pharmacogenomics approach for evaluating functions of transporters and ion channels in chemosensitivity and -resistance
Among the large number of transport proteins and potential drug substrates, only a fraction of the possible pharmacological interactions have been investigated. Even for known chemoresistance-associated transporters, a relatively small number of them have been extensively characterized for specific drug substrates. Availability of novel genomic technologies permits a global approach, pharmacogenomics, to revealing complex genetic factors in drug sensitivity [92]. Our laboratory has applied a
Conclusions
Multiple types of membrane transporters and channels play important roles in sensitivity and resistance to anticancer agents. Besides a direct transporter–substrate relationship, indirect mechanisms may also modulate chemosensitivity, for example, by providing nutrients to cancer cells and modulating apoptosis and electrochemical gradients. A chemogenomics approach correlating drug potency with transporter/channel expression in multiple tissues provides a wealth of information on
Acknowledgements
Research Support: Wolfgang Sadée was supported by NIH grant GM61390 and by funds from The Ohio State University. Ying Huang was supported by Food and Drug Administration.
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