Inhibition of Heat Shock Protein 90 with AUY922 Represses Tumor Growth in a Transgenic Mouse Model of Islet Cell Neoplasms

Volker Fendrich, Sven Wichmann, Dominik Wiese, Jens Waldmann, Matthias Lauth, Peter Rexin, Carolin L.-Lopez, Hans J. Schlitt, Detlef K. Bartsch, Sven A. Lang
2014 Neuroendocrinology  
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
more » ... 22 may provide a new option for therapy of islet cell neoplasms. Introduction Pancreatic neuroendocrine neoplasia (pNEN) represents a rare, but important subset of pancreatic neoplasms. These tumors account for 2-4% of all clinically detected pancreatic tumors. Their overall incidence is approximately 1 in 100,000 people per year [1] . pNENs present as either functional tumors, causing specific hormonal syndromes like Zollinger-Ellison syndrome or or- Key Words Heat shock protein 90 · AUY922 · Transgenic RIP1-Tag2 mice · Islet cell tumors 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 factorinduced 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%
doi:10.1159/000368610 pmid:25301256 fatcat:sgn36m2ebjegtn2g3hkkc2w2je