Enhancement of doxorubicin sensitivity in breast cancer cells by protopanaxadiols, biologically active metabolites in ginseng

Abstract

Ginseng has been utilized as a medicinal plant for thousands of years in human history. The pharmacological effects of ginseng have been shown in diverse diseases including diabetes, neurodegenerative diseases, and cancers. Ginsenosides, the biologically active saponins of ginseng, and their anti-cancer effects have been studied a lot in the world. According to the previous researches, protopanaxadiols (PPDs), or PPD type ginsenosides, restrain cancer growth by inhibition of proliferation, angiogenesis, invasion, and metastasis in various types of cancers. However, the detailed mechanisms of the ginsenosides to lead anti-cancer effects are not fully understood, so far. Meanwhile, in conventional anti-cancer therapy, adverse cytotoxic effects of the anti-cancer drugs to normal cells and acquiring drug-resistances of cancer cells are significant obstacles. Therefore, it is a critical issue to reduce the treatment dosage of anti-cancer drugs while increasing the cytotoxicity of the drugs for the cancer cells. In this research, I proposed highly effective adjuvant anti-cancer therapy using ginsenosides to sensitize cancer cells to anti-cancer drug. The results indicate that the two PPD type ginsenosides, compound-K (C-K) and protopanaxadiol (PPD), synergistically increase the cytotoxicity of doxorubicin in human breast cancer cell line, MCF-7. Although the ginsenosides did not cause any cell death in low concentration, the non-cytotoxic dose of the ginsenosides enhanced the doxorubicin sensitivity and increased caspase-9 dependent apoptotic cell death. The ginsenoside C-K and PPD induced mitochondrial fragmentation, and increased mitochondrial outer membrane permeability and cytochrome-c release. In summary, this study demonstrated that the non-cytotoxic concentration of ginsenoside C-K and PPD sensitized MCF-7 to mitochondria-mediated intrinsic apoptosis induced by doxorubicin via mitochondrial fragmentation.