Proteotoxic Stress Induced By Magnetic Fluid Hyperthermia (MFH) Enhances Bortezomib Cytotoxicity

Clinical studies have demonstrated the effectiveness of combined hyperthermia and anticancer drug treatment.  However, challenges related to effective heat transfer have limited its clinical application. The use of magnetic fluids to induce hyperthermia (MFH) has been an attractive treatment to overcome these challenges; however, the mechanism by which MFH enhances anticancer drugs cytotoxicity has not been explored in depth. In this work, studies of mechanisms involved in the synergistic potentiation of bortezomib in combination with magnetic fluid hyperthermia (MFH) were performed. Our hypothesis was that MFH can produce significant protein damage inducing cell death. To test the hypothesis, studies between hyperthermia and the proteasome inhibitor bortezomib for various cell lines (MDA-MB 468, Caco-2, and A2780) were conducted and results were compared with those of hot water hyperthermia. Aggresome formation and microtubule disruption as a function of recovery time in MCF-7 cells were done. Results show that there is a synergistic potentiation between hyperthermic treatment and bortezomib in all tested cell lines, but, MFH induced cell cytotoxicity in sensitive and resistant cell lines significantly higher than HWH.  Studies of aggresome formation and microtubule disruption indicated that MFH induces higher proteotoxic stress that hot water hyperthermia. This result suggests that this is one of the mechanisms by which MFH enhaces bortezomib cytotoxicity.