Increasing the rate of heating: A potential therapeutic approach for achieving synergistic tumour killing in combined hyperthermia and chemotherapy

Purpose: A synergistic cancer cell killing effect of sub-lethal hyperthermia and chemotherapy has been reported extensively. In this study, in vitro cell culture experiments with a uterine cancer cell line (MES-SA) and its multidrug resistant (MDR) variant MES-SA/Dx5 were conducted in order to investigate the role of heating rate in achieving a synergistic effect. The mode of cell death, induction of thermal tolerance and P-glycoprotein (P-gp) mediated MDR following two different rates of heating were studied. Materials and methods: Doxorubicin (DOX) was used as the chemotherapy drug. A rapid rate hyperthermia was achieved by near infrared laser (NIR) excited indocyanine green (ICG) dye (absorption maximum at 808 nm, ideal for tissue penetration). A slow rate hyperthermia was provided by a cell culture incubator. Results: The potentiating effect of hyperthermia to chemotherapy can be maximised by increasing the rate of heating. When delivered at the same thermal dose, a rapid increase in temperature from 37 degrees C to 43 degrees C caused more cell membrane damage than gradually heating the cells from 37 degrees C to 43 degrees C and thus allowed for more intracellular accumulation of DOX. Meanwhile, the rapid rate laser-ICG hyperthermia at 43 degrees C caused cell necrosis whereas the slow rate incubator hyperthermia at 43 degrees C induced mild apoptosis. At 43 degrees C a positive correlation between thermal tolerance and the length of hyperthermia exposure is identified. Conclusions: This study shows that by increasing the rate of heating, less thermal dose is needed in order to overcome P-gp mediated MDR.