Resveratrol Enhances Chemosensitivity in Mouse Melanoma Model Through Connexin 43 Upregulation

Abstract

Although current studies indicate that resveratrol exhibits potential antitumor activities, the precise mechanisms of its beneficial effects combined with chemotherapy are not fully understood. This work is warranted to elucidate the underlying mechanism of antitumor effects by the combination therapy of resveratrol and cisplatin. The presence of functional gap junctions is highly relevant for the success of chemotherapy. Gap junctions mediate cell communication by allowing the passage of molecules from one cell to another. Connexin (Cx) 43 is ubiquitous and reduced in a variety of tumor cells. Cx43 may influence the response of tumor cells to treatments by facilitating the passage of antitumor drugs or death signals between neighboring tumor cells. Following resveratrol treatment, dose-dependent upregulation of Cx43 expressions was observed. In addition, gap junction intercellular communication was increased. To study the mechanism underlying these resveratrol-induced Cx43 expressions, we found that resveratrol induced a significant increase in mitogen-activated protein kinases (MAPK) signaling pathways. The MAPK inhibitors significantly reduced the expression of Cx43 protein after resveratrol treatment. Specific knockdown of Cx43 resulted in a reduction of cell death after resveratrol and cisplatin treatment. Our results suggest that treatment of resveratrol in tumor leads to increase Cx43 gap junction communication and enhances the combination of resveratrol and cisplatin therapeutic effects. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 877-886, 2015.

Targeting drivers of melanoma with synthetic small molecules and phytochemicals

“…Resveratrol treatment enhanced cisplatin cytotoxicity in a mouse melanoma model, which was believed to occur through increased Connexin 43, a ubiquitous gap junction protein. 170 In another study, exposure of melanoma cells to resveratrol inhibited Ref-1-activated AP-1 DNA-binding and endonuclease activities, rendering melanoma cells more sensitive to dacarbazine treatment. 171 …”

“…170,193 Moreover, phytochemicals are remarkably nontoxic. The proposed mechanisms of these phytochemicals are yet to be fully elucidated, however, it has been proposed that due to their ubiquity in nature, through evolution, phytochemicals inherently possess diverse mechanisms of action.…”

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

“…It is now suggested that treatment with resveratrol increases Cx43 gap-junction communication, as a knockdown of Cx43 resulted in a reduction of cell death after treatment with both cisplatin and resveratrol. Additionally the MAPK signaling pathway was activated, and the use of MAPK inhibitors also decreased the expression of Cx43 protein [244]. …”

Resveratrol Sensitizes Colorectal Cancer Cells to Cetuximab by Connexin 43 Upregulation-Induced Akt Inhibition

“…It has a protective effect against angiogenesis in breast cancer cells (25), but significantly increases tubulogenesis when glioma cells are co-cultured with human umbilical vascular endothelial cells (26). Some studies indicate that resveratrol increases Cx43 expression and GJ in cancer cells such as those of hepatocellular carcinoma (27) and melanoma (28). Akt is one of the resveratrolassociated predicted targets on colorectal cancer (29) and is regulated by Cx43 in many cases of antitumor studies.…”