Regulatory players of DNA damage repair mechanisms: Role in Cancer Chemoresistance

Sakthivel, Kunnathur Murugesan; Subramanian, Hariharan

doi:10.1016/j.biopha.2017.07.035

“…Considerable evidence in solid tumors suggests that increased repair or tolerance of DNA lesions may contribute to the ability of cancer cells to survive in environments with high genotoxic stress 52 . Various oncogenes, cancer stem cells, a hypoxic environment, transcription factors and bystander signaling are activated in cancer cells, thus allowing for effective repair of DNA damage 53 . These repaired cancer cells are often more resistant to further treatment, thus leading to disease recurrence 53 .…”

Section: Resultsmentioning

confidence: 99%

“…Various oncogenes, cancer stem cells, a hypoxic environment, transcription factors and bystander signaling are activated in cancer cells, thus allowing for effective repair of DNA damage 53 . These repaired cancer cells are often more resistant to further treatment, thus leading to disease recurrence 53 . In this study, the genes associated with DNA damage repair were highly expressed, thereby suggesting that the recurrence of cancer and resistance might be due to DNA damage repair.…”

Section: Resultsmentioning

confidence: 99%

Single-cell RNA-seq reveals the immune escape and drug resistance mechanisms of mantle cell lymphoma

Wang

¹

,

Mo²,

Li

³

et al. 2020

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“…There are four mainly different DNA repair mechanisms: nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strain break repair (DSB) 10 . X-ray repair crosscomplementing protein 1 (XRCC1), belonging to the BER pathway, interacts with DNA polymerase-beta, DNA ligase III, and PARP (poly ADP-ribose polymerase) to repair damaged DNA, including platinum-induced damage 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis

Zhang

¹

,

Ouyang

²

,

Chang

³

et al. 2020

BioMed Research International

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Background. Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis. Methods. Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models. Results. Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln ( OR = 1.71 , 95% CI: 1.16-2.52, p = .007 , I 2 = 56.8 % ) and GlnArg ( OR = 1.23 , 95% CI: 1.07-1.40, p = .003 , I 2 = 29.0 % ) were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS ( HR = 0.60 , 95% CI: 0.40-0.88) and PFS ( HR = 0.64 , 95% CI: 0.46-0.90). We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles (TrpTrp vs. ArgArg: OR = 1.73 , 95% CI:1.31-2.27; TrpArg vs. ArgArg: OR = 1.28 , 95% CI: 1.06-1.55), suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS. Conclusion. Our results showed that rs25487 and rs1799782 of XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC.

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“…BIN1 binds to PARP1 and inhibits its activity. Decreased expression of BIN1 causes induction of PARP and can stimulate DNA repair 30 . On the other hand, it was shown that HO-1 induction or exposure to CO induces homologous recombination-mediated DNA repair through ataxia-telangiectasia mutated/ataxia telangiectasia and Rad3-related (ATM/ATR) protein 31 .…”

Section: Discussionmentioning

confidence: 99%

DNA damage and antioxidant properties of CORM-2 in normal and cancer cells

Juszczak

¹

,

Kluska

²

,

Wysokiński

³

et al. 2020

Sci Rep

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In this study, we compared the effect of tricarbonyldichlororuthenium (II) dimer (CORM-2) and its CO-depleted molecule (iCORM-2) on human peripheral blood mononuclear cells (PBMCs) and human promyelocytic leukemia HL-60 cells. We determined cell viability, DNA damage and DNA repair kinetics. We also studied the effect of both compounds on DNA oxidative damage, free radical level and HO-1 gene expression. We showed that at low concentrations both CORM-2 and iCORM-2 stimulate PBMCs viability. After 24-h incubation, CORM-2 and iCORM-2, at the concentration of 100 µM, reduce the viability of both PBMCs and HL-60 cells. We also demonstrated that CORM-2 and iCORM-2, in the 0.01-100 µM concentration range, cause DNA damage such as strand breaks and alkaline labile sites. DNA damage was repaired efficiently only in HL-60 cells. CORM-2 significantly reduces oxidative stress induced by 1 mM H 2 o 2 in normal and cancer cells. On the contrary, iCORM-2 in HL-60 cells increases the level of free radicals in the presence of 1 and 5 mM H 2 o 2. We also revealed that both CORM-2 and iCORM-2 induce HO-1 gene expression. However, CORM-2 induces this gene to a greater extent than iCORM-2, especially in HL-60 cells at 100 µM. Finally, we showed that CORM-2 and iCORM-2 reduce H 2 o 2-induced DNA oxidative damage. Furthermore, CORM-2 proved to be a compound with stronger antioxidant properties than iCORM-2. Our results suggest that both active CORM-2 and inactive iCORM-2 exert biological effects such as cyto-and genotoxicity, antioxidant properties and the ability to induce the HO-1 gene. The released CO as well as iCORM-2 can be responsible for these effects. Carbon monoxide (CO) is a colorless, tasteless and odorless gas produced by the burning of fuels and organic materials. It is reported to be the most frequent cause of fatal poisoning with an incidence rate of 31%. CO is readily absorbed and is unchanged by the lungs. CO demonstrates more than 200-fold stronger affinity for hemoglobin compared to oxygen. Therefore, even a small level of CO may cause poisoning. In contrast to hypoxiainducing toxic concentrations, a low dose of CO or even nanomolar concentrations exert biological activities. CO is produced in low amounts as a byproduct of normal human metabolism by the enzyme called heme oxygenase (HO-1) 1. CO has the ability to reduce the stimulation of guanylate cyclase to generate cyclic guanosine 3′,5′-monophosphate (cGMP). As a signaling molecule, CO modulates several p38 mitogen-activated protein kinase (MAPK)-related signaling pathways via both cGMP-dependent and independent processes, directly activates calcium-dependent potassium channels and induces protein kinase B (Akt) phosphorylation via the phosphatidylinositol 3-kinase/Akt pathway 2. Moreover, CO inhibits mitochondrial respiration by binding the ferrous heme a 3 in the active site of cyclooxygenase (COX), effectively shutting down oxidative phosphorylation, similar to the effects of cyanide and nitric oxide (NO) 3. The cGMP-dependent activity of CO includes inhibit...

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Regulatory players of DNA damage repair mechanisms: Role in Cancer Chemoresistance

Cited by 62 publications

References 53 publications

Single-cell RNA-seq reveals the immune escape and drug resistance mechanisms of mantle cell lymphoma

Single-cell RNA-seq reveals the immune escape and drug resistance mechanisms of mantle cell lymphoma

Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis

DNA damage and antioxidant properties of CORM-2 in normal and cancer cells

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