Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway

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Abstract
Novel strategies for overcoming multidrug resistance are urgently needed to improve chemotherapy success and reduce side effects. Ginsenosides, the main active components of Panax ginseng, display anti-cancer properties and reverse drug resistance; however, the biological pathways mediating this phenomenon remain incompletely understood. This study aimed to evaluate the anti-cancer effects of ginsenoside Rp1, actinomycin D (ActD), and their co-administration in drug-resistant cells and murine xenograft model of colon cancer, and explore the underlying mechanisms. ActD increased expression and activity of SIRT1 in drug-resistant LS513 colon cancer, OVCAR8-DXR ovarian cancer, and A549-DXR lung cancer cells, but not in ActD-sensitive SW620 colon cancer cells. Inhibition of SIRT1, either pharmacologically, with EX527 or through siRNA, stimulated p53 acetylation and apoptosis in LS513 cells when treated with ActD. ActD also increased AKT activation in drug-resistant cells. Inhibition of AKT abrogated ActD-induced upregulation of SIRT1, suggesting that the AKT-SIRT1 pathway is important in ActD resistance. Rp1 inhibited both ActD-induced AKT activation and SIRT1 upregulation and re-sensitized the cells to ActD. Synergistic antitumor effects of Rp1 with ActD were also observed in vivo. Our results suggest that combining Rp1 with chemotherapeutic agents could circumvent drug resistance and improve treatment efficacy.

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