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

الملخص EN

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.