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Oncol Lett. 2015 Feb;9(2):837-844. Epub 2014 Nov 19.

Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase C signaling pathway.

Author information

1
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China ; Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221006, P.R. China.
2
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
3
Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China ; Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China ; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
4
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China ; Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.

Abstract

Cantharidin is an active constituent of mylabris, a traditional Chinese therapeutic agent. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A). Cantharidin has been previously reported to efficiently repress the growth of pancreatic cancer cells. However, excessively activated protein kinase C (PKC) has been shown to improve cell survival following the adminstration of cantharidin. Tamoxifen is widely used in the treatment of estrogen receptor-positive breast cancer. In addition, an increasing number of studies have found that tamoxifen selectively inhibits PKC and represses growth in estrogen receptor-negative cancer cells. Administration of a combination of PKC inhibitor and PP2A inhibitors has been demonstrated to exert a synergistic anticancer effect. The proliferation of pancreatic cancer cells was analyzed by 3-(4,5-dimethyltiazol-2-yl]2, 5-diphenyltetrazo-lium bromide assay. The expression levels of ERα and ERβ in various pancreatic cancer cell lines were determined by reverse transcription polymerase chain reaction. In addition, the protein levels of PKCα and phosphorylated PKCα in pancreatic cell lines were analyzed by western blot analysis. In the present study, tamoxifen was found to exert a cytotoxic effect against pancreatic cancer cells independent of the hormone receptor status. Tamoxifen repressed the phosphorylation of PKC, and amplified the anticancer effect induced by cantharidin and norcantharidin. The findings reveal a novel potential strategy against pancreatic cancer using co-treatment with tamoxifen plus cantharidin or cantharidin derivatives.

KEYWORDS:

cantharidin; pancreactic cancer; protein kinase C; protein phosphatase 2A; tamoxifen

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