Sodium demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, characterized by a high degree of malignancy, a poor prognosis, and chemotherapy resistance. The Anticancer activities of cantharidin and its derivatives have been widely reported. Sodium demethylcantharidate is a derivative of cantharidin that shows excellent Anticancer activity against multiple types of Cancer, including HCC. However, its mechanism of action remains unclear. We evaluated the Anticancer activities of sodium demethylcantharidate in SMMC-7721 and Bel-7402 HCC cells in the current study and demonstrated that sodium demethylcantharidate effectively inhibited the proliferation of SMMC-7721 and Bel-7402 HCC cells in a dose- and time-dependent manner. Flow cytometry analysis showed that sodium demethylcantharidate could induce Apoptosis. Western blotting revealed that endoplasmic reticulum (ER) stress-related proteins (p-IRE1, GRP78/BiP, CHOP, the spliced form of XBP1, and caspase-12) were upregulated in SMMC-7721 and Bel-7402 cells after exposure to sodium demethylcantharidate. Based on those results, we confirmed that sodium demethylcantharidate could induce Apoptosis via ER stress. Moreover, a significant attenuation of SMMC-7721 cell tumorigenesis was observed after sodium demethylcantharidate treatment in a nude mouse xenograft model. These findings elucidate one mechanism underlying the Anticancer activity of sodium demethylcantharidate against HCC.