Paving the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics.
A new paper, High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice, has been published in MDPI. It explores the protective effect of hyperthermia on topoisomerase targeting therapeutics.
Cancer is a leading cause of mortality but it does not appear consistently across populations. Analysis of epidemiological data has uncovered an inverse pattern of geographical cancer distribution and annual temperature. Countries with low average annual temperatures exhibit the highest incidence of cancer. The two populations living in the coldest environments, Alaska Indians and Inuit, exhibit high cancer incidence. Although human thermoregulation systems sustain body core temperature at 37 °C, exposure to extreme or sustained temperatures overwhelms the body’s thermoregulatory capacity especially at old age, leading to hypothermia (<35 °C) or hyperthermia (>40.5 °C). How the changes in environmental and body temperature affect cancer development remains unclear.
Hyperthermia treatment, also known as thermotherapy, is an ancient treatment used to treat cancer, dating back to 5000 BC. Thermotherapy is applied by regionally heating the tumor to 40–45 °C. Hyperthermia induces a wide range of cellular effects, including mitotic dysfunction, cytoskeletal damage, alternations in membrane structure, metabolic dysfunction, DNA damage, interference with cell cycle, and protein denaturation. While noncancerous cells can tolerate temperatures up to 42–45 °C, cancerous cells are more susceptible. Hyperthermia therefore enhances the effectiveness of radiotherapy and chemotherapy.
The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in noncancerous cells.
One approach, as described above, is the acute exposure to hyperthermia, which suppresses DNA repair and synergizes with radiotherapy and chemotherapy. An exception, however, is the protective effect of hyperthermia on topoisomerase targeting therapeutics. The molecular explanation for this conundrum is unknown.
In this paper, we show that hyperthermia suppresses the level of topoisomerase mediated single- and double-strand breaks induced by exposure to topoisomerase poisons. We further uncover that, hyperthermia suppresses hallmarks of genomic instability induced by topoisomerase targeting therapeutics by inhibiting nuclease activities, thereby channeling repair to error-free pathways driven by tyrosyl-DNA phosphodiesterases.
These findings provide an explanation for the protective effect of hyperthermia from topoisomerase-induced DNA damage and may help to explain the inverse relationship between cancer incidence and temperature. They also pave the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics.
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