Norcantharidin Induces Melanoma Cell Apoptosis Through Tr3 Pathway

Norcantharidin (NCTD) is the demethylated analog of cantharidin, a naturally occurring toxin isolated from Mylabris. NCTD has been used to treat hepatocellular carcinoma with clinical efficacy and limited side effects. However, the underlying mechanism of its antitumor effects remains elusive. We have previously shown that TR3 expression is significantly decreased in metastatic melanomas and it is implicated in regulation of melanoma cell apoptosis. In this study, we showed that NCTD inhibited melanoma cell viability and induced apoptosis in vitro. NCTD induced translocation of TR3 from nucleus to mitochondria where it colocalized with Bcl-2 in melanoma cells. NCTD also increased Cytochome c release from mitochondria to the cytoplasm. There was also increased expression of Bax and cleaved caspase-3, accompanied with decreased expression of Bcl2 and Nf-kB2. The effects of NCTD were inhibited by knockdown TR3 expression in melanoma cells. To study its function in vivo, we treated Tyr::cre;BRAF Ca/+ ;Pten lox/lox mice with NCTD. Temozolomide and PBS were used as controls, and ten mice were used in each group. Temozolomide modestly increased mice survival, whereas NCTD significantly improved the survival of treated mice. Our data indicates that NCTD inhibits melanoma growth by inducing cell apoptosis via activation of a TR3 dependent pathway. These results suggest that NCTD is a potential therapeutic agent for melanoma. Financial support was provided by CA-093372, CA-116103 to XX. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5043. doi:10.1158/1538-7445.AM2011-5043