Stemona alkaloids, from traditional Thai medicine, increase chemosensitivity via P-glycoprotein-mediated multidrug resistance

Abstract P-glycoprotein-mediated drug efflux can cause a multidrug resistance (MDR) phenotype that is associated with a poor response to cancer chemotherapy. Through bioassay-guided fractionation, active Stemona alkaloids were isolated from the roots of Stemona aphylla and S. burkillii . The chemical structures of isolated alkaloids were confirmed by HPLC, LC–MS and NMR as stemocurtisine and oxystemokerrine from S. aphylla , and stemofoline from S. burkillii . The isolated alkaloids were evaluated for synergistic growth inhibitory effect with cancer chemotherapeutic agents including vinblastine, paclitaxel and doxorubicin of KB-V1 cells (MDR human cervical carcinoma with P-gp expression), but not in KB-3-1 cells (drug sensitive human cervical carcinoma, which lack P-gp expression). Verapamil was employed as a comparative agent. The results showed that among these three isolated alkaloids; stemofoline exhibited the most potent effect in vitro in the reversal of P-gp-mediated MDR. Treatment with stemofoline at the various concentrations up to 72 h was able to significantly increase sensitivity of anticancer drugs including vinblastine, paclitaxel and doxorubicin in dose- and time-dependent manner in KB-V1 cells. The result obtained from this study indicated that Stemona alkaloids may play an important role as a P-gp modulator as used in vitro and may be effective in the treatment of multidrug-resistant cancers. This is the first report of new pharmacological activity of Stemona alkaloids, which could be a new potential MDR chemosensitizer.