The combination of pro-oxidative acting vanicosides and GLUT1 inhibitor (WZB117) exerts a synergistic cytotoxic effect against melanoma cells.

Vanicosides A and B isolated from Reynoutria sachalinensis rhizomes are disaccharide phenylpropanoid esters with proven antioxidant activity. Our earlier study showed the cytotoxic activity of vanicosides against melanoma cells, but the mechanism of cell death has not been elucidated. Based on the chemical structure of vanicosides, we proposed that they may induce cell death by generating reactive oxygen species (ROS) into melanoma cells. Moreover, the glucose molecule in their structure can affect the glucose transporters (GLUTs), upregulated in cancer cells. The A375 (melanotic) and C32 (amelanotic) melanoma cell lines were applied. Cell viability assay and ROS-Glo™ assay were performed before and after blocking of Glucose Transporter Type 1 (GLUT1) by WZB117. Fibroblasts and the SKOV-3 line were included in the study to test selectivity in the action of vanicosides and help to elucidate the mechanism of action. Upon incubation with vanicosides, high production of ROS occured, especially inside C32 cells, which was significantly reduced after GLUT-1 blocking. The A375 cells produced less ROS. Melanoma cells were simillary sensitive to the cytotoxic effects of vanicosides, which was clearly enhanced when vanicosides were used together with the WZB117 (GLUT1 inhibitor). The SKOV-3 line and the fibroblasts showed much less sensitivity to the cytotoxicity of vanicosides, also used together with WZB117. Moreover, no significant ROS formation was observed in these lines. The study proved that vanicosides generate ROS inside melanoma cells. These findings suggest that the combination of pro-oxidative acting vanicosides and GLUT1 inhibitors exerts a synergistic cytotoxic effect on melanoma cells.