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Evidence-Based Complementary and Alternative Medicine
Volume 2013 (2013), Article ID 161628, 16 pages
http://dx.doi.org/10.1155/2013/161628
Research Article

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

1Graduate Institute of Life Sciences, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan
2Department 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
3Biobank Management Center of Tri-Service General Hospital, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan
4School of Pharmacy, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan
5Division of Urology, Tri-Service General Hospital, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan

Received 18 February 2013; Accepted 17 April 2013

Academic Editor: Shuang-En Chuang

Copyright © 2013 Jar-Yi Ho et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.