Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings. Vol 22, No 14S: 9663
Aglycone Protopanaxadiol, a ginseng saponin inhibits P-glycoprotein and sensitizes chemotherapy drugs on multidrug resistant cancer cells.
W. Jia, H. Yan, X. Bu, G. Liu, Y. Zhao;
University of British Columbia, Vancouver, BC, Canada; PanaGin Pharmaceuticals, Vancouver, BC, Canada
Background: Aglycone Protopanaxadiol (aPPD) is an aglycone derivative of ginseng saponins. Our previous work showed that a natural ginseng product CARESENGTM containing mainly aPPD induced cell apoptosis through various signal pathways including caspases. CARESENGTM also enhances the sensitivity of multidrug resistant cancer cells to various chemotherapy drugs. P-glycoprotein (P-gp, MDR1) is one of the major causes of multidrug resistance of many tumor cells. Blocking the function of P-gp may enhance efficacy of chemotherapy. In the present study, we investigated the possible mechanism of chemosensitizing effect of purified aPPD compound as well as CARESENGTM.
Methods: Breast cancer cell MCF-7adr and leukemia cell line P388adr, both overexpressing P-gp, were used to test the interaction between the compound and P-gp. Calcein-AM, a P-gp substrate, efflux assay was used to measure function of P-gp. Membrane preparation was also used to measure the ATPase activity of P-gp in the presence of aPPD or verapamil.
Results: Our results demonstrated that 70uM aPPD could significantly block P-gp function on both MCF-7adr and P388adr cells showing increased intracellular concentrations of calcein-AM. Furthermore, the maximum effects of aPPD and verapamil on P-gp inhibition was additive when treated together on P388adr cells. On the other hand, aPPD had no effect on ATPase activity of P-gp while verapamil increased it by more than 2-fold. 20uM of aPPD completely reversed P-gp induced drug resistant to Taxol or Doxorubicin on MCF-7adr cells. CARESENGTM gave rise to similar results in all the above experiments.
Conclusions: These results suggest that aPPD is an effective P-gp blocker with a mechanism different from that of verapamil. Given extremely low toxicity of the compound, aPPD is a potential candidate of chemosensitizer for treatment of multidrug resistant tumors.