Toward a new approach to treating tumors: Inducing apoptosis by combining chemotherapy and mild hyperthermia

Our studies on the effects of mild hyperthermia (≤ 42°C) on prometaphase-arrested and interphase HeLa cells are reviewed. Mild heat treatment rapidly induces apoptosis in H-HeLa cells that have been arrested in prometaphase with spindle poisons. This is shown by the appearance of morphological changes characteristic of apoptosis, the activation of Caspase 3, and the fact that the changes are blocked by caspase inhibitors such as zVAD-fmk. The same treatment does not cause apoptosis in interphase cells, or in prometaphase-arrested cells of other HeLa strains such as HeLa S3, MKF, and WML. However, prometaphase-arrested cultures of those other HeLa strains can be made sensitive to mild heat treatment by simultaneous exposure to compounds such as navitoclax (ABT-263) which inhibit Bcl-2 family anti-apoptotic proteins. Interphase cells can be made sensitive to 42°C treatment by combining ABT-263 or ABT-199 with S63845, a potent and selective inhibitor of MCL-1. These studies suggest that it might be possible to find a treatment for tumors that combines systemic drug treatment with localized hyperthermia. Clues to how that might be achieved are discussed.