Ovatodiolide targets β -catenin signaling in suppressing tumorigenesis and overcoming drug resistance in renal cell carcinoma

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Abstract

Dysregulated β-catenin signaling is intricately involved in renal cell carcinoma (RCC) carcinogenesis and progression. Determining potential β-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for β-catenin signaling inhibitors involved in silico inquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell lines in vitro and 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound of Anisomeles indica, inhibited β-catenin signaling and reduced RCC cell viability, survival, migration/invasion, and in vitro cell or in vivo mouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylated β-catenin (S552) that inhibited β-catenin nuclear translocation. Moreover, ovatodiolide decreased β-catenin stability and impaired the association of β-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent β-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy. © 2013 Jar-Yi Ho et al.

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Ho, J. Y., Hsu, R. J., Wu, C. L., Chang, W. L., Cha, T. L., Yu, D. S., & Yu, C. P. (2013). Ovatodiolide targets β -catenin signaling in suppressing tumorigenesis and overcoming drug resistance in renal cell carcinoma. Evidence-Based Complementary and Alternative Medicine, 2013. https://doi.org/10.1155/2013/161628

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