Protopanaxadiols, active ingredients of ginseng, enhance doxorubicin-induced cytotoxicity in human breast cancer cells via modulation of mitochondrial dynamics

Abstract

Ginseng has been utilized as a medicinal plant for thousands of years for various human diseases including cancers. Anti-cancer effects of ginseng have been considered to be mediated by ginsenosides, the biologically active saponins of ginseng. Among ginsenosides, protopanaxadiols (PPDs) have been revealed to restrain cancer progression by inhibition of proliferation, angiogenesis, invasion, and metastasis in various types of cancers. However, the detailed mechanisms of the ginsenosides for anti-cancer effects are not fully understood so far. In this study, two PPD-type ginsenosides, compound-K (C-K) and protopanaxadiol (PPD), synergistically increased the cytotoxicity of doxorubicin in MCF-7 human breast cancer cells. The enhancement of the doxorubicin sensitivity was induced by caspase-9 dependent apoptotic cell death. We further demonstrated that mitochondrial fragmentation and cytochrome-c release from mitochondria are responsible for the ginsenoside-induced sensitization to doxorubicin. In summary, we demonstrated that the non-cytotoxic dose of ginsenoside C-K and PPD sensitized MCF-7 breast cancer cells to mitochondria-mediated intrinsic apoptosis induced by doxorubicin via mitochondrial fragmentation.