Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells.

Through extensive screening of marine sponge compounds, the authors have found that sipholenol A, a sipholane triterpene isolated from the Red Sea sponge, Callyspongia siphonella, potently reversed multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). In experiments, sipholenol A potentiated the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine, and paclitaxel, but not the non-P-gp substrate cisplatin, and significantly reversed the MDR of cancer cells KB-C2 and KB-V1 in a concentration-dependent manner. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MDR protein 1 or breast cancer resistance protein. Sipholenol A (IC(50) > 50 microM) is not toxic to all the cell lines that were used, regardless of their membrane transporter 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 alter the expression of P-gp after treating KB-C2 and KB-V1 cells for 36 h and 72 h. However, it efficaciously stimulated the activity of ATPase of P-gp and inhibited the photolabeling of this transporter with its transport substrate [(125)I]-iodoarylazidoprazosin. Overall, the present results indicate that sipholenol A efficiently inhibits the function of P-gp through direct interactions, and sipholane triterpenes are a new class of potential reversing agents for treatment of MDR in P-gp-overexpressing tumors.