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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.

Ovatodiolide Targetsβ-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma