The x cϪ cystine/glutamate antiporter has been implicated in GSH-based chemoresistance because it mediates cellular uptake of cystine/cysteine for sustenance of intracellular GSH levels. Celastrol, isolated from a Chinese medicinal herb, is a novel heat shock protein 90 (Hsp90) inhibitor with potent anticancer activity against glioma in vitro and in vivo. In search of correlations between growth-inhibitory potency of celastrol in NCI-60 cell lines and microarray expression profiles of most known transporters, we found that expression of SLC7A11,

The cystine-glutamate transporter SLC7A11 has been implicated in chemoresistance, by supplying cystine to the cell for glutathione maintenance. In the NCI-60 cell panel, SLC7A11 expression shows negative correlation with growth inhibitory potency of geldanamycin but not with its analog 17-(allylamino)-17-demethoxygeldanamycin (17

These observations demonstrate that GA analogues are substrates as well as inhibitors of ABCB1, suggesting that drug interactions between GA analogues and other agents that are ABCB1 substrates may occur via ABCB1 in normal or tumor cells.

These results suggest that elevated expression of MRP1, like the alternative efflux transporter MDR1 (ABCB1, P-glycoprotein), can significantly influence tumor cell sensitivity to geldanamycins as a potential chemoresistance factor.

Background : The importance of transporters in drug disposition and response has led to increasing interest in genetic variations and expression differences of their genes. Objective : This review summarizes: i) genetic variations in transporters and associated drug response; and ii) a pharmacogenomic approach to correlate transporter expression and drug response. Methods : Several transporters in ATP-binding cassette family and solute carrier family are discussed. Conclusion : The field of transporter pharmacogenomics is in its early stage. Transporter expression at mRNA levels could be more directly related to their functions and more practical to be assayed in high throughput. Correlating microarray expression of transporters with anticancer drug activity in the NCI-60 panel has provided an approach for identifying drug-transporter relationships and predicting drug response.