DNA damage and the circadian clock

Chakarov, Stoyan; Petkova, Rumena; Russev, George; Zhelev, Nikolai

doi:10.7750/biodiscovery.2014.13.1

Cited by 3 publications

(4 citation statements)

References 268 publications

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“…The DDR preserves genetic stability by detecting DNA lesions, activating cell cycle checkpoints and promoting DNA damage repair [18][19][20][21]. The common denominator integrating these forms of genotoxic stresses and eliciting the signalling cascade is increased production of ROS as harbinger to DNA damage [22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM-and ATR-dependent DDR and NRF2-mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both ATM and ATR expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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Section: Introductionmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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“…Shi et al pointed out the enhanced DMN‐ACN functional connectivity was involved in sustained hypervigilance and hyperarousal, and it could reflect the function of self‐reflection, emotional regulation and cognitive control. Also, the cortisol secretion levels of MCPs were significantly higher than ECPs at 10 h after awakening, 45 which may be manifested by heightened arousal, including hypersensivity to various stimuli and/or hypervigilance 46 . Moreover, MCPs showed a higher total amount of cortisol and there was a significantly shortened phase of cortisol increase within the first hour after awakening, 47 which suggested that MCPs may increase cortisol secretion levels after a longer period of awakening and enhance arousal.…”

Section: Discussionmentioning

confidence: 92%

“…Also, the cortisol secretion levels of MCPs were significantly higher than ECPs at 10 h after awakening, 45 which may be manifested by heightened arousal, including hypersensivity to various stimuli and/or hypervigilance. 46 Moreover, MCPs showed a higher total amount of cortisol and there was a significantly shortened phase of cortisol increase within the first hour after awakening, 47 which suggested that MCPs may increase cortisol secretion levels after a longer period of awakening and enhance arousal. Although stronger anti‐correlation of rsFC between DMN and ACN may be accompanied by better performance, it may also represent mere negative emotion and arousal.…”

Section: Discussionmentioning

confidence: 98%

Distinct neural responses of morningness and eveningness chronotype to homeostatic sleep pressure revealed by resting‐state functional magnetic resonance imaging

et al. 2022

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Sleep-wake activity is regulated by two processes of circadian rhythm (C) and sleep homeostatic (S), which is known as the CS model. 1 The process of circadian rhythm leads to rhythmic changes in sleep preferences within 24 h. During homeostatic process, homeostatic sleep pressure (HSP) accumulates with the increase of waking time and dissipates during sleep. 2 Sleep homeostatic and circadian rhythm play an important role in mental health and even pathology. 3,4 Chronotype is a appropriate variable to investigate

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“…14 Higher efficacy and better tolerability of timed platinum-based systemic chemotherapy have been demonstrated in several experimental models. [15][16][17][18][19] Hyperthermic intraperitoneal chemoperfusion (HIPEC) is a type of locoregional chemotherapy which is used in combination with cytoreductive surgery for certain types of cancer affecting the peritoneum. 20 Local hyperthermia along with high doses of the drugs enhances the penetration of the drugs into residual tumor nodes left after surgery.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Systemic and Locoregional Cisplatin Chronotherapy in Rats with Ovarian Carcinoma

Kireeva¹,

Губарева²,

Maydin³

et al. 2021

OTT

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Aim: Alterations in circadian rhythms caused by tumor growth are thought to be clinically relevant as they affect the prognosis and treatment response. We aimed to evaluate the chronotherapeutic approach in rats with ovarian cancer receiving cisplatin intravenously (IV) or with hyperthermic intraperitoneal chemoperfusion (HIPEC) and to assess daily variations in tumor and intestinal epithelium proliferation. Methods: In the pilot study, we used 12 intact rats and 12 rats with transplantable ovarian cancer, which were euthanized at ZT0 (08:00, lights on), ZT6, ZT12 and ZT18. In the main study, we used 45 rats with transplantable ovarian cancer. Animals were randomized into five groups: control, HIPEC with cisplatin at ZT0 (08:00), HIPEC with cisplatin at ZT12 (20:00), IV cisplatin at ZT0 and IV cisplatin at ZT12. We assessed the proliferation rate of tumor and small intestinal epithelium, apoptosis in small intestinal epithelium, and levels of γ-H2AX (DNA damage/repair marker) in kidneys and liver. Survival was calculated in each group. Results: Ascitic ovarian cancer disrupted daily variations in intestinal epithelium proliferation and DNA damage/repair in rats. Ovarian carcinoma exhibited no daily variation in mitotic activity. In animals receiving IV cisplatin, massive cell damage in the renal medulla and cystic changes within renal tubules were observed, unlike in rats receiving HIPEC. Tumor mitotic activity was lower in morning-treated groups. The median survival of rats in the control group was 8.5 days (95% CI 6.0-22.0), in HIPEC at ZT0 40.5 days (95% CI 28.0-47.0, p<0.001) and in HIPEC at ZT12 32.0 days (95% CI 28.0-37.0, p<0.001). Conclusion:In a rat model, ovarian tumor growth disrupted daily variations in intestinal epithelium proliferation and caused genotoxic stress in tumor-free tissues. HIPEC with cisplatin at ZT0 had a better efficacy/toxicity profile than HIPEC with cisplatin at ZT12 and IV administration at both time points.

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DNA damage and the circadian clock

Cited by 3 publications

References 268 publications

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Distinct neural responses of morningness and eveningness chronotype to homeostatic sleep pressure revealed by resting‐state functional magnetic resonance imaging

Efficacy and Safety of Systemic and Locoregional Cisplatin Chronotherapy in Rats with Ovarian Carcinoma

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