Cantharidin and norcantharidin impair stemness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib

Author：

Publisher： Spandidos Publications

E-ISSN： 1791-2423|47|5|1912-1922

ISSN： 1019-6439

Source： International Journal of Oncology, Vol.47, Iss.5, 2015-01, pp. : 1912-1922

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Abstract

Increasing evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth, and are hypothesized to account for therapeutic resistance. Based on the expression of the surface markers CD44, CD24, and EPCAM, putative CSCs have also been identified in pancreatic cancers. It has been well established that aberrant activation of β-catenin signaling pathway may contribute to the maintenance of CSCs. Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. In our previous studies, we demonstrated that cantharidin treatment induced phosphorylation of β-catenin, leading to repression on β-catenin pathway. Therefore, in the present study, we investigated whether cantharidin and its derivant, norcantharidin, could repress the stemness of pancreatic cancer cells through repression on β-catenin pathway. By using microarray and flow cytometry, we found that treatment with cantharidin and norcantharidin repressed the expression of CD44, CD24, and EPCAM at both mRNA and protein levels, leading to decreased CD44+/CD24+/EPCAM+ proportion, the putative pancreatic CSC subset. Pretreatment with the β-catenin pathway inhibitor FH535, attenuated the cantharidin- and norcantharidin-inducrd repression on CD44, CD24, and EPCAM, suggesting cantharidin and its derivant repressed stemness of pancreatic cancer cells in β-catenin pathway-dependent manner. Furthermore, cantharidin and norcantharidin strengthened the cytotoxicity of gemcitabine and erlotinib, two well established pharmacotherapeutics against pancreatic cancers, indicating cantharidin and norcantharidin could be promising candidates for reversing drug resistance in pancreatic cancers. In conclusion, we presently propose that cantharidin and norcantharidin hold their promise in pancreatic cancer therapy through repression on stemness and strengthening the cytotoxicity of the present therapeutics.