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Ovatodiolide Targets {Beta} -Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma.

Ho JY, Hsu RJ, Wu CL, Chang WL, Cha TL, Yu DS, Yu CP.

Evid Based Complement Alternat Med. 2013;2013:161628.

 

Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan ; Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan.

 

Abstract

Dysregulated {Beta} -catenin signaling is intricately involved in renal cell carcinoma (RCC) carcinogenesis and progression. Determining potential {Beta} -catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening for {Beta} -catenin signalinginhibitors 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 {Beta} -catenin signaling and reduced RCCcell 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 {Beta} -catenin (S552) that inhibited {Beta} -catenin nuclear translocation. Moreover,ovatodiolide decreased {Beta} -catenin stability and impaired the association of {Beta} -catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potent {Beta} -catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.

 

 

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