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Evid Based Complement Alternat Med. 2013;2013:161628. doi: 10.1155/2013/161628. Epub 2013 May 26.

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

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  • 1Graduate 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 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.

PMID:
23781255
[PubMed]
PMCID:
PMC3677612
Free PMC Article
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