Hyperthermia and Pharmacological Intervention of Heat Shock Proteins in Anticancer Treatments

Civilization-associated diseases, including cancers, are the result of cellular adaptation to microenvironments aided by the high expression of heat shock proteins (Hsps). Knowledge of tumor biology has exploded during the last few decades, and this has led to the development of target based drug discovery. These target based anticancer drugs act by blocking cell proliferation and by inducing cytostasis which is followed by the apoptosis of tumor cells. Being central regulators of cellular homeostasis, and by helping tumor cells to escape from stress induced cell death, Hsps have been recognized as pharmacological targets for anticancer treatments. Hsp inhibitors elicit their effects through the inhibition of the chaperone functions of Hsps, thus attacking multiple cellular signaling pathways. Inhibiting stress responses not only inhibits Hsp synthesis but sensitizes tumor cells to chemotherapeutic agents. Hyperthermia has been used as a treatment for several pathological states and diseases to improve recovery rates ; thus tumor cells that have defective stress responses can be sensitized to apoptosis using hyperthermia or heat shock. Selective combination of anti-Hsp drugs with hyperthermia have been shown to have the desired cytostatic/cytotoxic effects in some tumor models. A discussion of the effects of enforced apoptosis using anti-Hsp inhibitors, and facilitated apoptosis using hyperthermia, either alone or in combination, is presented.