Wrzal, P. K., Bettaieb, A. and Averill-Bates, D. A. Molecular Mechanisms of Apoptosis Activation by Heat Shock in Multidrug-Resistant Chinese Hamster Cells. Radiat. Res. 170, 498–511 (2008).

Multidrug resistance (MDR) is a major obstacle to the success of chemotherapy in cancer treatment and is associated with overexpression of P-glycoprotein. MDR cells, aside from resistance to chemotherapy, might also inhibit apoptosis at various levels in the death signaling pathways. Currently, hyperthermia is used in cancer treatment to sensitize tumor cells to radiation and/or chemotherapy. This study investigated the induction of death receptor and mitochondria-mediated signaling pathways of apoptosis by hyperthermia (41–43°C) in MDR CH^RC5 cells compared to drug-sensitive AuxB1 Chinese hamster ovary cells. In the receptor-mediated pathway, CH^RC5 cells exhibited higher levels of c-FLIP and lower caspase 8 and caspase 10 activation in response to hyperthermia. In the mitochondria-mediated pathway of heat-induced apoptosis, CH^RC5 cells showed higher mitochondrial levels of Bax and tBid, more pronounced mitochondrial membrane depolarization, and increased Apaf-1. Similar levels of caspase 3 activation and cleavage of caspase substrates occurred, showing that overall, CH^RC5 cells are not resistant to hyperthermia-induced apoptosis compared to AuxB1 cells. This study reveals for the first time the molecular mechanisms of hyperthermia-induced apoptosis in MDR cells overexpressing P-glycoprotein. CH^RC5 and AuxB1 cells showed similar clonogenic survival responses to heat, which implies that hyperthermia could be a promising strategy for eradicating MDR tumor cells in the clinic.