Boosting the effects of hyperthermia-based anticancer treatments by HSP90 inhibition
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Lianne E.M. Vriend1,2,3,*, Nathalie van den Tempel4,*, Arlene L. Oei2,3,*, Mike L’Acosta1, Frederique J. Pieterson1, Nicolaas A.P. Franken2,3, Roland Kanaar4 and Przemek M. Krawczyk1,2,3
1Department of Medical Biology, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
2Department of Radiation Oncology, Laboratory of Experimental Oncology and Radiobiology (LEXOR), Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
3Cancer Center Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
4Department of Molecular Genetics, Cancer Genomics Center Netherlands, Department of Radiation Oncology, Erasmus Medical Center, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
*These authors have contirbuted equally to this work
Przemek M. Krawczyk, email: firstname.lastname@example.org
Keywords: hyperthermia; HSP90 inhibition; DNA repair; thermotolerance; ganetespib
Received: July 22, 2017 Accepted: August 26, 2017 Published: October 27, 2017
Hyperthermia – application of supra-physiological temperatures to cells, tissues or organs – is a pleiotropic treatment that affects most aspects of cellular metabolism, but its effects on DNA are of special interest in the context of cancer research and treatment. Hyperthermia inhibits repair of various DNA lesions, including double-strand breaks (DSBs), making it a powerful radio- and chemosensitizer, with proven clinical efficacy in therapy of various types of cancer, including tumors of head and neck, bladder, breast and cervix. Among the challenges for hyperthermia-based therapies are the transient character of its effects, the technical difficulties in maintaining uniformly elevated tumor temperature and the acquisition of thermotolerance. Approaches to reduce or eliminate these challenges could simplify the application of hyperthermia, boost its efficacy and improve treatment outcomes. Here we show that a single, short treatment with a relatively low dose of HSP90 inhibitor Ganetespib potentiates cytotoxic as well as radio- and chemosensitizing effects of hyperthermia and reduces thermotolerance in cervix cancer cell lines. Ganetespib alone, applied at this low dose, has virtually no effect on survival of non-heated cells. Our results thus suggest that HSP90 inhibition can be a safe, simple and efficient approach to improving hyperthermia treatment efficacy and reducing thermotolerance, paving the way for in vivo studies.
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