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Abstract
Membrane transporters and channels (collectively the transportome) govern cellular influx and efflux of ions, nutrients, and drugs. We used oligonucleotide arrays to analyze gene expression of the transportome in 60 human cancer cell lines used by the National Cancer Institute for drug screening. Correlating gene expression with the potencies of 119 standard anticancer drugs identified known drug-transporter interactions and suggested novel ones. Folate, nucleoside, and amino acid transporters positively correlated with chemosensitivity to their respective drug substrates. We validated the positive correlation between SLC29A1 (nucleoside transporter ENT1) expression and potency of nucleoside analogues, azacytidine and inosine-glycodialdehyde. Application of an inhibitor of SLC29A1, nitrobenzylmercaptopurine ribonucleoside, significantly reduced the potency of these two drugs, indicating that SLC29A1 plays a role in cellular uptake. Three ABC efflux transporters (ABCB1, ABCC3, and ABCB5) showed significant negative correlations with multiple drugs, suggesting a mechanism of drug resistance. ABCB1 expression correlated negatively with potencies of 19 known ABCB1 substrates and with Baker's antifol and geldanamycin. Use of RNA interference reduced ABCB1 mRNA levels and concomitantly increased sensitivity to these two drugs, as expected for ABCB1 substrates. Similarly, specific silencing of ABCB5 by small interfering RNA increased sensitivity to several drugs in melanoma cells, implicating ABCB5 as a novel chemoresistance factor. Ion exchangers, ion channels, and subunits of proton and sodium pumps variably correlated with drug potency. This study identifies numerous potential drug-transporter relationships and supports a prominent role for membrane transport in determining chemosensitivity. Measurement of transporter gene expression may prove useful in predicting anticancer drug response.
Highlights
Membrane transporters, ion exchangers, and ion channels are encoded by numerous gene families, comprising ϳ4% of genes in the human genome, with 406 genes encoding ion channels and 883 encoding a broad variety of transporters, of which, 350 are intracellular transporters [1]
Membrane transporters play key roles in pharmacology, affecting the entry of drugs into cells and ovarian cell lines in the panel showed a similar negative correlation, it was hypothesized that a subset of ovarian cancer patients might benefit from L-asparaginase treatment
Each of the 60 cell line samples was studied by array experiment once, with each probe spotted on the same array four times, using RNA samples obtained from the National Cancer Institute (NCI), to ensure that the cells were under the same conditions and passage numbers as used in a previous cDNA microarray study [9]
Summary
Ion exchangers, and ion channels are encoded by numerous gene families, comprising ϳ4% of genes in the human genome, with 406 genes encoding ion channels and 883 encoding a broad variety of transporters, of which, 350 are intracellular transporters [1]. Focus on solute carriers (SLCs), ABC transporters acting as extrusion pumps, ion transport ATPases, and select ion channel and pore families In combination, these genes encode a majority of proteins involved in membrane transport, of drugs. These genes encode a majority of proteins involved in membrane transport, of drugs We applied those arrays to a study of the NCI-60 cells and correlated the resulting expression patterns with potency data for a set of 119 anticancer agents with putatively known mechanisms of action [7]. This analysis established numerous significant drug-transporter relationships. This study provides a basis for additional exploration of drug transport pathways and for optimizing cancer chemotherapy
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