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 72h 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.

Keywords: Stemona aphylla, Stemona burkillii, Stemocurtisine, Oxystemokerrine, Stemofoline, P-glycoprotein