Reversal of P-gp-mediated multidrug resistance in colon cancer by cinobufagin.

Cinobufagin (CBF) is isolated from the skin and posterior auricular glands of the Asiatic toad (Bufo gargarizans). This study investigated the reversal effect of CBF on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in colon cancer. The effect of CBF on the cytotoxicity of anticancer drugs in P-gp overexpressing LoVo/ADR, HCT116/L, Cao-2/ADR cells and their parental cells was determined using CCK-8 assay. Apoptosis of anti-cancer drugs and accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho123) in P-gp overexpressing cells were evaluated by flow cytometry. Results indicated that CBF significantly enhanced the sensitivity of P-gp substrate drugs on P-gp overexpressing cells, but had no effect on their parental cells. CBF enhanced the effect of DOX against P-gp-overexpressing LoVo/ADR cell xenografts in nude mice. Moreover, CBF also increased cell apoptosis of chemotherapy agents and intracellular accumulation of DOX and Rho123 in the MDR cells. Further research on the mechanisms revealed non-competitive inhibition of P-gp ATPase activity, but without altering the expression of P-gp. These findings demonstrated that CBF could be further developed into a safe and potent P-gp modulator for combination use with anticancer drugs in cancer chemotherapy.