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.
References (100)
- et al.
Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study
Blood
(1999) - et al.
MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models
Blood
(2003) - et al.
Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters
Toxicology
(2001) - et al.
Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1)
Bioorg. Med. Chem. Lett.
(2002) - et al.
MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2’,3’-dideoxycytidine and 9’-(2’-phosphonylmethoxyethyl)adenine
J. Biol. Chem.
(2003) - et al.
ABCG2 – a transporter for all seasons
FEBS Lett.
(2004) - et al.
Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump
Blood
(2004) - et al.
MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping
J. Biol. Chem.
(2000) - et al.
Regulation of Progenitor Cell Fusion by ABCB5 P-glycoprotein, a Novel Human ATP-binding Cassette Transporter
J. Biol. Chem.
(2003) - et al.
Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells
Cancer Cell
(2004)
The cellular pharmacology of methotrexate
Pharmacol. Ther.
Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells
J. Biol. Chem.
Reduced folate carrier gene silencing in multiple antifolate-resistant tumor cell lines is due to a simultaneous loss of function of multiple transcription factors but not promoter methylation
J. Biol. Chem.
Methylation-dependent silencing of the reduced folate carrier gene in inherently methotrexate-resistant human breast cancer cells
J. Biol. Chem.
Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib)
J. Biol. Chem.
Nucleoside transporters: molecular biology and implications for therapeutic development
Mol. Med. Today
L-type amino acid transporter-1 overexpression and melphalan sensitivity in Barrett's adenocarcinoma
Neoplasia
Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery
J. Pharm. Sci.
Role of organic cation transporters in the renal secretion of nucleosides
Biochem. Pharmacol.
Resistance mechanisms associated with altered intracellular distribution of anticancer agents
Pharmacol. Ther.
Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro
Biochem. Pharmacol.
Identification of a new chondropsin class of antitumor compound that selectively inhibits V-ATPases
J. Biol. Chem.
Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents
J. Biol. Chem.
Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs
Crit. Rev. Oncol. Hematol.
Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene
Cancer Cell.
Drug uptake and pharmacological modulation of drug sensitivity in leukemia by AQP9
Biochem. Biophys. Res. Commun.
Drug sensitivity and resistance genes in cancer chemotherapy: a chemogenomics approach
Drug Discovery Today
Mining our ABCs: pharmacogenomic approach for evaluating transporter function in cancer drug resistance
Cancer Cell
ABC transporters in lipid transport
Biochim. Biophys. Acta.
Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease
Cell
The sequence of the human genome
Science
Multidrug resistance in cancer: role of ATP-dependent transporters
Nat. Rev. Cancer
Mining the National Cancer Institute's tumor-screening database: identification of compounds with similar cellular activities
J. Med. Chem.
Expression of a multidrug resistance gene in human cancers
J. Natl. Cancer Inst.
P-glycoprotein: from genomics to mechanism
Oncogene
Membrane Transporters and Channels: Role of the Transportome in Cancer Chemosensitivity and Chemoresistance
Cancer Res.
Chemo-resistance to depsipeptide FK228 is mediated by reversible MDR1 induction in human cancer cell lines
J. Pharmacol. Exp. Ther.
Clinical aspects of the MDR1 (ABCB1) gene polymorphism
Ther. Drug Monit.
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line
Science
The MRP family of drug efflux pumps
Oncogene
ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P
Mol. Pharmacol.
Expression of the multidrug resistance-associated protein (MRP) gene in human cancers
Clin. Cancer Res.
RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response
Clin. Cancer Res.
Anticancer multidrug resistance mediated by MRP1: Recent advances in the discovery of reversal agents
Med. Res. Rev.
A multidrug resistance transporter from human MCF-7 breast cancer cells
Proc. Natl. Acad. Sci. USA
Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)
Oncogene
Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro
Cancer Res.
Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells
Cancer Res.
Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter
Cancer Res.
Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein
Cancer Res.
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