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Research Articles: Therapeutics, Targets, and Development

A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells

¹ Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio and ² Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky

Requests for reprints: Duxin Sun, Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210. Phone: 614-292-4381; Fax: 614-292-7766. E-mail: sun.176{at}osu.edu

Abstract

Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu³³ (Hsp90) and Arg¹⁶⁷ (Cdc37). Immunoprecipitation confirmed that celastrol (10 µmol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 µmol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 µmol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells. [Mol Cancer Ther 2008;7(1):162–70]

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³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁴ Unpublished data.

Received 7/18/07; revised 10/23/07; accepted 11/28/07.