Ginsenoside Rg3 enhances the chemosensitivity of tumors to cisplatin by reducing the basal level of nuclear factor erythroid 2-related factor 2-mediated heme oxygenase-1/NAD(P)H quinone oxidoreductase-1 and prevents normal tissue damage by scavenging cisp

The clinical use of cisplatin (cis-diamminedichloroplatinum II) has been limited by the frequent emergence of cisplatin-resistant cell populations and numerous other adverse effects. Therefore, new agents are required to improve the therapy and health of cancer patients. Oral administration of ginsenoside Rg3 significantly inhibited tumor growth and promoted the anti-neoplastic efficacy of cisplatin in mice inoculated with CT-26 colon cancer cells. In addition, Rg3 administration remarkably inhibited cisplatin-induced nephrotoxicity, hepatotoxicity and oxidative stress. In cell-based experiments, Rg3 inhibited cisplatin-induced cytotoxicity in LLC-RK1 kidney and NCTC1469 liver cells but not in CT-26 cancer cells and significantly decreased cisplatin-induced intracellular ROS levels in these cells. In normal cells with cytoplasmically localized Nrf2 and negligible levels of HO-1 and NQO-1, Rg3 substantially decreased cisplatin-induced elevation in HO-1/NQO-1 levels and inhibited cisplatin-induced translocation of Nrf2 into the nucleus. In chemoresistant cancer cells with high levels of HO-1/NQO-1 and nuclear Nrf2, both basal and cisplatin-induced levels of HO-1/NQO-1 and nuclear Nrf2 were decreased by Rg3 treatment, thereby enhancing the susceptibility of cancer cells to cisplatin. Collectively, Rg3 promotes the efficacy of cisplatin by inhibiting HO-1 and NQO-1 expression in cancer cells and protects the kidney and liver against tissue damage by preventing cisplatin-induced intracellular ROS generation.

► Cancer cells constitutively show high levels of Nrf2 in nucleus and HO-1/NQO-1. ► Nrf-2 in cytoplasm and very low levels of HO-1/NQO-1 are detected in normal cells. ► Rg3 reduces both basal and cisplatin-induced HO-1/NQO-1 levels in cancer cells. ► The reduced HO-1/NQO-1 below control levels enhances the susceptibility to cisplatin. ► Nephro- and hepatoprotective effect of Rg3 is linked to its ROS scavenging activity.