A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

Kinzel L, Ernst A, Orth M, Albrecht V, Hennel R, Brix N, Frey B, Gaipl U, Zuchtriegel G, Reichel CA, Blutke A, Schilling D, Multhoff G, Li M, Niyazi M, Friedl AA, Winssinger N, Belka C, Lauber K (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Oncotarget Impact Journals

Book Volume: 7

Pages Range: 43199-43219

Journal Issue: 28

DOI: 10.18632/oncotarget.9774

Abstract

The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo.

Authors with CRIS profile

Benjamin Frey Department of Radiation Oncology Udo Gaipl Department of Radiation Oncology

Involved external institutions

Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) University of Geneva / Université de Genève (UNIGE) CH Switzerland (CH)

How to cite

APA:

Kinzel, L., Ernst, A., Orth, M., Albrecht, V., Hennel, R., Brix, N.,... Lauber, K. (2016). A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer. Oncotarget, 7(28), 43199-43219. https://dx.doi.org/10.18632/oncotarget.9774

MLA:

Kinzel, Linda, et al. "A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer." Oncotarget 7.28 (2016): 43199-43219.

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