Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all

Abstract

The currently available arsenal of anticancer modalities includes many DNA damaging agents that can kill malignant cells. However, efficient DNA repair mechanisms protect both healthy and cancer cells against the effects of treatment and contribute to the development of drug resistance. Therefore, anti-cancer treatments based on inflicting DNA damage can benefit from inhibition of DNA repair. Hyperthermia – treatment at elevated temperature – considerably affects DNA repair, among other cellular processes, and can thus sensitize (cancer) cells to DNA damaging agents. This effect has been known and clinically applied for many decades, but how heat inhibits DNA repair and which pathways are targeted has not been fully elucidated. In this review we attempt to summarize the known effects of hyperthermia on DNA repair pathways relevant in clinical treatment of cancer. Furthermore, we outline the relationships between the effects of heat on DNA repair and sensitization of cells to various DNA damaging agents.

Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms

“…However, the spectrum of different lesions induced by a single DNA damaging agent, as well as the possibility that hyperthermia targets multiple DNA repair pathways, prevents conclusive interpretation of data obtained using this genetic approach. Indeed, multiple DNA repair pathways, such as base excision repair [66] for single strand DNA lesions and non-homologous end joining for double strand breaks [100], are believed to be inhibited by hyperthermia [96]. However, the results obtained in these studies are often based on experiments done with temperatures above 43 C, so it remains unclear whether inhibition of these DNA repair pathways add to the effects of mild hyperthermia.…”

“…Moreover, heating cells to 41.5 C increased the amount of phosphorylation of histone H2AX (cH2AX), which is considered a marker for DNA double strand breaks [99]. However, there is also a large body of literature that describes hyperthermia as having no direct damaging effect on DNA, but rather interferes with the activity of proteins important for repairing DNA caused by an exogenous agent, such as radiotherapy ( Figure 1E) [96].…”

“…The mechanism by which hyperthermia sensitises to DNA damaging agents has been extensively studied, but the results are often difficult to interpret because of the use of different temperatures and an overlap in the several DNA damage repair pathways. The many hypotheses that consider what effects hyperthermia has on DNA have recently been reviewed [96].…”

Targeting therapy-resistant cancer stem cells by hyperthermia

“…Hyperthermia not only inhibits repair of DNA damage caused by radiation but also suppresses AKT signalling, a radiation-induced survival mechanism preferentially utilised by the CSC population [167]. Second, it is becoming clear that hyperthermia can induce DNA damage by causing protein denaturation and interfering with DNA replication (reviewed by Oei et al [168]). There has been a long debate whether hyperthermia induces DNA damage or not, as increased (unrepaired) DNA damage is observed after combinational therapies that include hyperthermia in nearly all studies that tested the effectiveness of hyperthermia.…”

“…Direct methods to detect immediate induction of DNA breaks failed in most of the studies as mild hyperthermia interferes predominantly with DNA repair pathways. Therefore, the effects of hyperthermia on (unrepaired) DNA damages may therefore be caused by indirect effects ( [169] and reviewed by Oei et al [168]). …”