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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

Authors
Kinzel, Linda
Ernst, Anne
Orth, Michael
Albrecht, Valerie
Hennel, Roman
Brix, Nikko
Frey, Benjamin
Gaipl, Udo S.
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Published in Oncotarget. 2016, vol. 7, no. 28, p. 43199-43299
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.
Keywords HSP90 inhibitionRadiosensitizationColorectal cancerDNA damage responseCell death
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Other version: http://www.oncotarget.com/abstract/9774
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Research group Groupe Winssinger
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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. In: Oncotarget, 2016, vol. 7, n° 28, p. 43199-43299. https://archive-ouverte.unige.ch/unige:85394

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Deposited on : 2016-07-20

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