Reversal of multidrug resistance by novel inhibitors of human P‐glycoprotein in cell culture (974.2)

Abstract

Multidrug resistance (MDR) and chemotherapy failure are often due to overexpression of members of the ABC‐transporter superfamily of proteins like MDR1 P‐glycoprotein (P‐gp). These membrane transporters protect cells from the accumulation of harmful toxins by using ATP hydrolysis to move a broad range of compounds across the plasma membrane. In MDR, however, the administration of chemotherapeutics selects for cancerous cells which overexpress P‐gp thereby creating a population of cancer cells resistant to many types of chemotherapeutics. Using targeted molecular dynamic simulations and massively parallel drug docking studies, we have identified several novel compounds that inhibit transport by P‐gp by targeting the ATP binding domains. Biochemical and biophysical studies have shown that these inhibitors do indeed bind to the nucleotide binding domains of P‐gp and inhibit ATP hydrolysis. In the studies reported here, we have been able to re‐sensitize MDR prostate and ovarian cancer cell lines in culture to multiple chemotherapeutics when treated with the novel compounds. The compounds reverse the MDR phenotype to sensitivities similar to the original, non‐MDR parental cell lines. Limited toxicity was observed when non‐cancerous cells were treated with the P‐gp inhibitors alone. The results suggest that these novel P‐gp inhibitors may serve as good drug leads for treating MDR and chemotherapy failure.Grant Funding Source: Supported by NIH/NIGMS 1R15GM094771 ‐ 01A1 to PDV and JGW and the Communities Foundation of Texas