Boosting the effects of hyperthermia-based anticancer treatments by HSP90 inhibition

Abstract

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.