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Scientific article
English

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

Published inOncotarget, vol. 7, no. 28, p. 43199-43299
Publication date2016
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 inhibition
  • Radiosensitization
  • Colorectal cancer
  • DNA damage response
  • Cell death
Research group
Citation (ISO format)
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. doi: 10.18632/oncotarget.9774
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ISSN of the journal1949-2553
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Creation07/19/2016 10:13:00 AM
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