Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein-mediated multidrug mesistance in cancer cells

2288 The marine ecosystem represents most of the species on the earth, and marine organisms provide numerous sources to develop novel compounds with multiple pharmacological potentials, including antiviral, antibacterial, anti-inflammatory, and anticancer and so on. The analgesic Conotoxin MVIIA (Prialt®) represents the first marine natural product drug to be introduced to the market. A number of marine compounds are currently in various phases of human clinical trials to treat different cancers, such as ecteinascidin, squalamine, aplidin, bryostatin-1, dolastatin-10 and ILX651. In this study, we screened thirty new marine sponge compounds to investigate their anticancer effects and inhibition of the activity of P-glycoprotein (P-gp, ABCB1) to reverse multidrug resistance (MDR) in human cancer cells. When these compounds were tested in two human drug-selected MDR cell lines KB-C2 and KB-V1, we found that one of the sipholane triterpenes, sipholenol A, in a concentration-dependent manner potentiated the cytotoxicity of several anticancer drugs including colchicine, vinblastine, and paclitaxel and significantly reversed the resistance of MDR cancer cells. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing other MDR-linked transporters including MRP1 (ABCC1) or breast cancer resistance protein (BCRP, ABCG2), and was not cytotoxic by itself at 50 μM, regardless of P-gp status. Accumulation and efflux studies with the P-gp substrate [ 3 H]-paclitaxel demonstrated that sipholenol A time-dependently increased the intracellular accumulation of [ 3 H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. In addition, sipholenol A did not have any effect on the expression of P-gp after treating MDR cancer cells for seventy-two hours, however, it did inhibit the photolabeling of P-gp with [ 125 I]- Iodoarylazidoprazosin. We conclude that sipholenol A interacts directly with P-gp and sipholane triterpenes are a new class of potential reversing agents for treatment of MDR in P-gp overexpressing tumors.