Components of Panax notoginseng saponins enhance the cytotoxicity of cisplatin via their effects on gap junctions

Previously, Panax notoginseng saponin (PNS)-induced enhancement of gap junction (GJ) formation or function was observed to be responsible for the increased cytotoxic action of cisplatin. PNS has three constituents, ginsenoside Rg1 and Rb1, and notoginsenoside R1. The active compounds in PNS responsible for enhancing the cytotoxicity of cisplatin remain unknown. Thus, the effects of the main components of PNS on the cytotoxicity of cisplatin were investigated, as well as the correlation with the modulation of GJ function in transfected He La cells. The cytotoxicity of cisplatin (0.25-1 mu g/ml) was increased in the presence of GJs. By contrast, the cytotoxicity of cisplatin was decreased when GJs were inhibited by a GJ blocker or by the inhibition of connexin expression. Ginsenoside Rg1 (100 mu M) and notoginsenoside R1 (100 mu M) were observed to significantly enhance cisplatin cytotoxicity in cells with functional GJs. Ginsenoside Rb1 had no effect on the cytotoxicity of cisplatin in the presence or absence of functional GJs. Cell exposure to ginsenoside Rg1 and notoginsenoside R1 for 4 h led to significant enhancement of a dye-coupled GJ in a dose-dependent manner; however, no effect was observed in cells exposed to ginsenoside Rb1. The present results indicate that ginsenoside Rg1 and notoginsenoside R1 are the active compounds responsible for enhancing the cytotoxic action of cisplatin induced by PNS in the presence of functional GJs.