Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1.

To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI-National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations-indicative of MDR1-mediated resistance-were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.