Abstract 1527: Pharmacogenomic identification of compounds selectively killing multidrug-resistant cancer cells with high glutathione metabolism

The ability of cancer cells to become simultaneously resistant to different drugs - a trait known as multidrug resistance (MDR) - remains a significant impediment to successful cancer therapy. Cancer cells develop MDR via several possible mechanisms, including (1) extrusion of drugs by increasing activity of efflux transporters, (2) reduction of drug uptake and (3) activation of detoxifying pathways such as those mediated by glutathione (GSH). SLC7A11 encodes a subunit of a transporter, designated x c − , which is responsible for cellular uptake of the amino acid cystine in exchange for intracellular glutamate. Once inside the cell, cystine is rapidly reduced to cysteine, a rate limiting precursor for biosynthesis of GSH. Using a pharmacogenomic approach, we have previously demonstrated that increased expression of SLC7A11 confers GSH-mediated resistance of tumor cells to anticancer drugs, since its expression level was negatively correlated with drug potency across the National Cancer Institute9s 60 cancer cell lines (NCI-60). The number of significant SLC7A11-drug correlations was much greater than those of known resistance genes such as ABCB1 and GSTs. To further investigate the role of SLC7A11 on chemosensitivity, we analyzed the correlation between SLC7A11 expression and activity of 1,400 chemical compounds on the NCI-60 and identified 39 compounds with positive SLC7A11 correlations. Interestingly, many of these compounds are analogs of the anticancer drug ellipticinium. All the eight ellipticinium analogs among the 1,400 compounds showed significant positive correlations with SLC7A11, while all the ellipticine analogs had no such correlation. Since the positive gene-drug correlation suggests that cell lines with higher SLC7A11 expression and higher GSH metabolism showed higher sensitivity to ellipticiniums, these compounds could exploit, rather than suppress the GSH pathways to increase tumor chemosensitivity. We examined the effect of the x c − transporter inhibitor sulfasalazine on SLC7A11 over-expressing and drug resistant glioma cell lines SNB-19 and SF-295. Sulfasalazine treatment (0.15 mM) significantly reduced the cytotoxicity of ellipticiniums but not that of ellipticines, consistent with the results obtained by the pharmacogenomic analysis. In view of the above exciting results, further investigations are being conducted to validate the interaction between the x c − transporter and ellipticinium analogs and to study the mechanism of the selective cytotoxicity. It may be feasible to take advantage of high level of SLC7A11 (or other genes in the GSH regulatory pathway) in some tumors for targeted cancer therapy. Taken together, the discovery of the MDR-selective compounds among the ellipticinium analogs demonstrated the robustness of the developing field of MDR-targeting therapy as a new strategy for overcoming GSH-mediated MDR. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1527.