Cellular responses to hyperthermia (40-46 degrees C): cell killing and molecular events.

The goal of this review is to provide a brief introduction to the effects of hyperthermia on cellular structures and physiology. The review focuses on the effects of hyperthermia thought to contribute to the enhancement of cancer therapy namely the mechanisms of cell killing and the sensitization of cells to ionizing radiation or chemotherapeutic agents. Specifically the review addresses four topics: hyperthermia induced cell killing, mathematical models of cell killing, mechanisms of thermal effects in the hyperthermia temperature range and effects on proteins that contribute to resistance to other stresses, i.e., DNA damage. Hyperthermia has significant effects on proteins including unfolding, exposing hydrophobic groups, and aggregation with proteins not directly altered by hyperthermia. Protein aggregation has effects throughout the cell but has a significant impact within the nucleus. Changes in the associations of nuclear proteins particularly those involved in DNA replication cause the stalling of DNA replication forks and lead to the induction of DNA damage such as double strand breaks. It has long been recognized that heat has effects on plasma membrane protein distribution alters the permeability of plasma membranes resulting in a calcium spike and disrupts the mitochondrial membrane potential resulting in the change in the redox status of cells. These effects contribute to the protein unfolding effects of hyperthermia and contribute to effects observed in the nucleus. Thus heat effects on multiple cellular targets can be integrated through global effects on protein folding to affect specific end points such as cell killing and sensitization to additional stresses.