Heat exposure enhances radiosensitivity by depressing DNA-PK kinase activity during double strand break repair

Ihara, Masataka; Takeshita, Satoshi; Okaichi, Kumio; Okumura, Yutaka; Ohnishi, Takeo

doi:10.3109/02656736.2014.887793

Cited by 49 publications

(43 citation statements)

References 41 publications

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“…It was later suggested that hyperthermia can act as a radio-sensitizer by interfering with the repair of DSBs as it may have an impact on c-NHEJ, alt-NHEJ and HR collectively [93]. Recent work showed that exposure to hyperthermia can restrict the activity of DNA-PKs in addition to reducing protein levels of KU70, KU80, BRCA1 and 53BP1 with the first two in greater extent [94]. Finally, given that various chemotherapeutic agents have the ability to trigger the induction of DSBs, inhibitors of DNA ligases and/or DNA-PKs appear to sensitize tumor cells to chemotherapeutic drugs thus providing alternative therapeutic strategies which potentially can be more effective [95,96].…”

Section: Non-homologous End Joining (Nhej)mentioning

confidence: 99%

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

Mantso

Goussetis

Franco

et al. 2016

Seminars in Cancer Biology

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Utilization of thermal therapy (hyperthermia) is defined as the application of exogenous heat induction and represents a concept that is far from new as it goes back to ancient times when heat was used for treating various diseases, including malignancies. Such therapeutic strategy has gained even more popularity (over the last few decades) since various studies have shed light into understanding hyperthermia's underlying molecular mechanism(s) of action. In general, hyperthermia is applied as complementary (adjuvant) means in therapeutic protocols combining chemotherapy and/or irradiation both of which can induce irreversible cellular DNA damage. Furthermore, according to a number of in vitro, in vivo and clinical studies, hyperthermia has been shown to enhance the beneficial effects of DNA targeting therapeutic strategies by interfering with DNA repair response cascades. Therefore, the continuously growing evidence supporting hyperthermia's beneficial role in cancer treatment can also encourage its application as a DNA repair mitigation strategy. In this review article, we aim to provide detailed information on how hyperthermia acts on DNA damage and repair pathways and thus potentially contributing to various adjuvant therapeutic protocols relevant to more efficient cancer treatment strategies.

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Section: Non-homologous End Joining (Nhej)mentioning

confidence: 99%

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

Mantso

Goussetis

Franco

et al. 2016

Seminars in Cancer Biology

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“…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.…”

Section: Hyperthermia and Dna Repairmentioning

confidence: 68%

Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms

Tempel¹,

Horsman

Kanaar³

2016

International Journal of Hyperthermia

101

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It has long been established that hyperthermia increases the therapeutic benefit of radiation and chemotherapy in cancer treatment. During the last few years there have been substantial technical improvements in the sources used to apply and measure heat, which greatly increases enthusiasm for the clinical use of hyperthermia. These advances are converging with a better understanding of the physiological and molecular effects of hyperthermia. Therefore, we are now at a juncture where the parameters that will influence the efficacy of hyperthermia in cancer treatment can be optimised in a more systematic and rational manner. In addition, the novel insights in hyperthermia's many biological effects on tumour cells will ultimately result in new treatment regimes. For example, the molecular effects of hyperthermia on the essential cellular process of DNA repair suggest novel combination therapies, with DNA damage response targeting drugs that should now be clinically explored. Here, we provide an overview of recent studies on the various macroscopic and microscopic biological effects of hyperthermia. We indicate the significance of these effects on current treatments and suggest how they will help design novel future treatments. ARTICLE HISTORY

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“…Several lines of evidence show that factors involved in DSB repair are likely to be affected by heat shock, for example, Ku heterodimer (Ku70/Ku80) [33][34][35][36], MRN complex [37][38][39], breast cancer susceptibility gene 1 (BRCA1) [40], BRCA2 [41] and RAD51 [41,42]. Heat shock affects these proteins by causing denaturation, cytoplasmic translocation from the nucleus, and protein degradation by the proteasome pathway [43].…”

Section: Discussionmentioning

confidence: 99%

Homologous recombination preferentially repairs heat-induced DNA double-strand breaks in mammalian cells

Takahashi

Mori

Nakagawa

et al. 2016

International Journal of Hyperthermia

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Purpose: Heat shock induces DNA double-strand breaks (DSBs), but the precise mechanism of repairing heat-induced damage is unclear. Here, we investigated the DNA repair pathways involved in cell death induced by heat shock. Materials and methods: B02, a specific inhibitor of human RAD51 (homologous recombination; HR), and NU7026, a specific inhibitor of DNA-PK (non-homologous end-joining; NHEJ), were used for survival assays of human cancer cell lines with different p53-gene status. Mouse embryonic fibroblasts (MEFs) lacking Lig4 (NHEJ) and/or Rad54 (HR) were used for survival assays and a phosphorylated histone H2AX at Ser139 (cH2AX) assay. MEFs lacking Rad51d (HR) were used for survival assays. SPD8 cells were used to measure HR frequency after heat shock. Results: Human cancer cells were more sensitive to heat shock in the presence of B02 despite their p53-gene status, and the effect of B02 on heat sensitivity was specific to the G 2 phase. Rad54-deficient MEFs were sensitive to heat shock and showed prolonged cH2AX signals following heat shock. Rad51d-deficient MEFs were also sensitive to heat shock. Moreover, heat shock-stimulated cells had increased HR. Conclusions: The HR pathway plays an important role in the survival of mammalian cells against death induced by heat shock via the repair of heat-induced DNA DSBs. ARTICLE HISTORY

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Heat exposure enhances radiosensitivity by depressing DNA-PK kinase activity during double strand break repair

Cited by 49 publications

References 41 publications

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies

Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms

Homologous recombination preferentially repairs heat-induced DNA double-strand breaks in mammalian cells

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