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
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Linda Kinzel1,*, Anne Ernst1,*, Michael Orth1,*, Valerie Albrecht1, Roman Hennel1, Nikko Brix1, Benjamin Frey2, Udo S. Gaipl2, Gabriele Zuchtriegel3, Christoph A. Reichel3, Andreas Blutke4, Daniela Schilling5, Gabriele Multhoff5, Minglun Li1, Maximilian Niyazi1, Anna A. Friedl1, Nicolas Winssinger6, Claus Belka1 and Kirsten Lauber1
1 Department of Radiation Oncology, Ludwig-Maximilians-University Munich, Munich, Germany
2 Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
3 Department of Otorhinolaryngology, Head and Neck Surgery, and Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
4 Institute of Veterinary Pathology at the Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
5 Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
6 Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland
* These authors share equal first authorship
Kirsten Lauber, email:
Keywords: HSP90 inhibition, radiosensitization, colorectal cancer, DNA damage response, cell death
Received: October 11, 2015 Accepted: May 24, 2016 Published: June 01, 2016
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.
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