Abstract
Heat shock protein 90 (Hsp90) has been identified to be crucial for stability and functionality of oncogenic signaling molecules, including EGFR, Her-2, Akt, Erk, and various transcription factors. Here we investigated growth inhibitory effects of a novel synthetic Hsp90 inhibitor (EC154) in gastrointestinal cancers.
Human pancreatic cancer cells, gastric cancer cells and endothelial cells were employed. Cytotoxic effects were assessed by MTT analyses. Effects of Hsp90 blockade on signaling pathways were investigated by Western blotting. The impact of EC154 on cell migration was evaluated in modified Boyden chambers. Effects of EC154 tumor growth and vascularization were investigated in subcutaneous xenograft models. The drug dose-dependently reduced proliferation of gastric and pancreatic cancer cells in vitro and Western blot analyses showed that EC154 effectively blocked STAT3, Akt and Erk activation in cancer cells, in addition to down-regulating EGFR and IGF-IR. Furthermore, EC154 led to marked inhibition of tumor cell migration in vitro. Interestingly, in endothelial cells (EC), EC154 not only significantly reduced cell survival/proliferation in MTT analyses, but also markedly decreased VEGFR2 activation and STAT3 phosphorylation. In addition, EC154 significantly reduced VEGF-A mediated EC migration in vitro. In vivo, treatment with EC154 significantly reduced tumor growth rates of both pancreatic and gastric cancer cells.
In conclusion, EC154 is a novel potent inhibitor of Hsp90 that effectively disrupts multiple oncogenic signaling cascades in gastric and pancreatic cancer cells, and significantly reduces tumor growth in vivo. Moreover, direct effects of EC154 on endothelial cells suggested that EC154 could be used for antineoplastic and antiangiogenic therapy in gastric and pancreatic cancer.
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Literatur
Neckers L (2002) Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8: 55–61
Zhang H, Burrows F (2004) Targeting multiple signaling transduction pathways through inhibition of Hsp90. J Mol Med 82: 488–499
Lang SA, Klein D, Moser C, Gaumann A, Glockzin G, Dahlke MH, Dietmaier W, Bolder U, Schlitt HJ, Geissler EK, Stoeltzing O (2007) Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. Mol Cancer Ther 6(3): 1123–1132
Lang SA, Moser C, Gaumann A, Klein D, Glockzin G, Popp FC, Dahlke MH, Piso P, Schlitt HJ, Geissler EK, Stoeltzing O (2007) Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I-receptor signaling, disrupts an interleukin-6/signal transducer and activator of transcription 3/hypoxia-inducible factor-1α autocrine loop, and reduces orthotopic tumor growth. Clin Cancer Res 13(21): 6459–6468
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© 2008 Springer Medizin Verlag Heidelberg
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Moser, C. et al. (2008). Inhibition von Heat-shock Protein 90 (Hsp90) mittels EC154, einem neuen synthetischen Hsp90 Antagonist, reduziert das Wachstum von humanen Magen- und Pankreaskarzinomzellen in vivo . In: Arbogast, R., Schackert, H.K., Bauer, H. (eds) Chirurgisches Forum 2008. Deutsche Gesellschaft für Chirurgie, vol 37. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-78833-1_37
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DOI: https://doi.org/10.1007/978-3-540-78833-1_37
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-78821-8
Online ISBN: 978-3-540-78833-1
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