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- Title
Inhibition of Heat Shock Protein 90 with AUY922 Represses Tumor Growth in a Transgenic Mouse Model of Islet Cell Neoplasms.
- Authors
Fendrich, Volker; Wichmann, Sven; Wiese, Dominik; Waldmann, Jens; Lauth, Matthias; Rexin, Peter; L.-Lopez, Carolin; Schlitt, Hans J.; Bartsch, Detlef K.; Lang, Sven a.
- Abstract
Background: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. Material and Methods: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. Results: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. Conclusion: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms. © 2014 S. Karger AG, Basel
- Subjects
HEAT shock proteins; TUMOR growth prevention; ISLET cell tumor; TRANSGENIC mice; LABORATORY mice
- Publication
Neuroendocrinology, 2015, Vol 100, Issue 4, p300
- ISSN
0028-3835
- Publication type
Article
- DOI
10.1159/000368610