Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy

The alkylating agent temozolomide (TMZ) is the major chemotherapeutic drug used clinically in the treatment of malignant gliomas. This study investigated the mechanism behind TMZ-induced cell death and the possibility that resveratrol might increase TMZ efficacy. TMZ induced both apoptotic cell death and cytoprotective autophagy through a reactive oxygen species (ROS) burst and extracellular signal-regulated kinase (ERK) activation, which was suppressed by resveratrol, resulting in a decrease in autophagy and an increase in apoptosis, suggesting that the ROS/ERK pathway plays a crucial role in the fate of cells after TMZ treatment. Isobolographic analysis indicated that the combination of TMZ and resveratrol has a synergistic effect. Moreover, an in vivo mouse xenograft study also showed that coadministration of resveratrol and TMZ reduced tumor volumes by suppressing ROS/ERK-mediated autophagy and subsequently inducing apoptosis. Taken together, our data indicate that TMZ-induced ROS/ERK-mediated autophagy protected glioma cells from apoptosis, and the combination of resveratrol with TMZ could improve the efficacy of chemotherapy for brain tumors.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (117 K)Download as PowerPoint slideHighlights► Temozolomide (TMZ) induces both apoptosis and autophagy in the glioma cells. ► ROS/ERK-mediated autophagy induced by TMZ plays a pro-survival role. ► Resveratrol enhances TMZ-induced apoptosis by inhibiting ROS and autophagy. ► Resveratrol exhibits a synergistic effect on TMZ-mediated cytotoxicity. ► Co-administration of resveratrol and TMZ reduces tumor volumes in vivo.