The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells

Chen, Ping; Li, Jian; Chen, Yongchang; Qian, Hai; Chen, Yu-Jiao; Su, Jinyu; Wu, Min; Lan, Ting

doi:10.1007/s13402-016-0291-7

Cited by 41 publications

(51 citation statements)

References 47 publications

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“…It is thought that interstrand cross‐links can do more harm to DNA replication and transcription than intrastrand cross‐links; therefore, fewer interstrand cross‐links may also contribute greatly to the toxicity of platinum agents . Complex DNA repair pathways participate in resolving DNA interstrand cross‐links, including translesion DNA synthesis (TLS), the Fanconi anemia (FA) pathway and homologous recombination (HR), thus regulating the cellular response to cisplatin . Recent studies have revealed novel roles of base excision repair (BER) and mismatch repair (MMR) pathways in activating interstrand cross‐links and therefore modulating cisplatin cytotoxicity rather than activating damage repair .…”

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confidence: 99%

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Zheng

Deng

Yin

et al. 2017

Intl Journal of Cancer

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Genetic variations in genes involved in repairing platinum-induced DNA lesions may contribute to the toxicity of platinum-based chemotherapy. The role of single-nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross-links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum-based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at p < 0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779 and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with severe gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR = 0.677, 95% CI: 0.510-0.899, p = 0.007; OR = 0.565, 95% CI: 0.368-0.869, p = 0.009; OR = 0.628, 95% CI: 0.439-0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum-induced toxicities.

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confidence: 99%

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Zheng

Deng

Yin

et al. 2017

Intl Journal of Cancer

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“…These data suggested that ERCC1 might be one of targets by which eHSA weakened the anticancer effect of DDP. We suspect there are another pathway regulate efficacy of DDP which altered by HSA (Chen et al, 2016). eHSA might weaken anticancer effect of VP-16 via up-regualting TOP2A exclusively.…”

Section: Discussionmentioning

confidence: 99%

Weakening Impact of Excessive Human Serum Albumin (eHSA) on Cisplatin and Etoposide Anticancer Effect in C57BL/6 Mice with Tumor and in Human NSCLC A549 Cells

et al. 2016

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Excessive human serum albumin (eHSA) impact on anticancer effects is inconsistent. We explored the outcome of cisplatin (DDP)/etoposide (VP-16) plus eHSA in vivo and in vitro. C57BL/6 mice with tumor were used to compare the efficacy of DDP/VP-16 alone and DDP/VP-16+eHSA. Blood albumin was measured to confirm whether eHSA elevate its level. Western blotting assay were used to measure the expression of ERCC1/TOP2A in tumor tissues. Cell proliferation, mRNA, and protein expression of ERCC1/TOP2A were also assayed to compare two groups in A549 cells. Furthermore we evaluated eHSA impact on cell proliferation in RNAi targeting ERCC1/TOP2A in A549 cells, respectively. eHSA reduced the anticancer effect of DDP/VP-16 without altering albumin level, increased protein expression of ERCC1/TOP2A, respectively in mice. Similarly, eHSA increased mRNA and proteins expression of ERCC1/TOP2A in A549 cells. In RNAi A549 cells, however, eHSA no longer weakened but enhanced the anticancer effect of DDP, while no longer altered the effect of VP-16. Our findings suggested that eHSA weaken the anticancer effect of DDP/VP-16 via up-regulating ERCC1/TOP2A expression, respectively. Further molecular mechanism studies are warranted to investigate whether eHSA is not conducive to lung cancer chemotherapy.

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“…NSCLC cell lines A549 and Calu‐1 (two human lung adenocarcinoma cell lines), SK‐MES‐1 (a human lung squamous carcinoma cell line), and A549/Cis (a cisplatin‐resistant A549 cell line) were purchased from the Shanghai Institute for Biological Science (China). A549/Cis cells were established by continuous exposure to increasing concentration of cisplatin for a 10‐month period (Chen et al, ). The cells were cultured in RPMT 1640 media supplemented with 10% heat‐inactivated fetal calf serum (FCS), L‐glutamin and 100 unit/ml penicillin/streptomycin at 37°C in humidified 5% CO2 incubator.…”

Section: Methodsmentioning

confidence: 99%

“…The modified alkaline comet assay was performed to determine ICL form as previously reported (Chen et al, ). After transfection with various siRNAs, cells were treated with cisplatin and then harvested.…”

Section: Methodsmentioning

confidence: 99%

“…γH2AX foci, P‐ATM foci, and RPA foci were detected by immunofluorescence assay as previously described (Chen et al, ; Dai et al, ). The resulting fluorescence images were captured on an Eclipse E400 fluorescence microscope (Nikon, Japan) and analyzed using Metafer software (MetaSystems), or Spot Advanced RT software (Diagnostic Instruments, Sterling Heights, MI).…”

Section: Methodsmentioning

confidence: 99%

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Knockdown of REV3 synergizes with ATR inhibition to promote apoptosis induced by cisplatin in lung cancer cells

Jiang

Chen

et al. 2017

Journal Cellular Physiology

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It has been demonstrated that REV3, the catalytic subunit of the translesion synthesis (TLS) polymerase ζ, play an important role in DNA damage response (DDR) induced by cisplatin, and Ataxia-telangietasia mutated and Rad-3-related (ATR) knase is a central player in activating cell cycle checkpoint, stabilizing replication forks, regulating DDR, and promoting repair of DNA damage caused by cisplatin. Cancer cells deficient in either one of REV3 and ATR are more sensitive to cisplatin. However, whether co-inhibition of REV3 and ATR can further increase sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin is not clear. In this study, we show that REV3 knockdown combined with ATR inhibition further enhance cytotoxicity of cisplatin in NSCLC cells, including cisplatin-sensitive and -resistant cell lines, compared to individual knockdown of REV3 or ATR, which are accompanied by markedly caspase-dependent apoptosis response, pronounced DNA damage accumulation and severe impediment of interstrand crosslink (ICL), and double strand break (DSB) repair. Our results suggest that REV3 knockdown synergize strongly with ATR inhibition to significantly increase sensitivity of cisplatin in NSCLC cells by inhibiting ICL and DSB repair. Thus simultaneously targeting REV3 and ATR may represent one approach to overcome cisplatin resistance and improve chemotherapeutic efficacy in NSCLC treatment.

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The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells

Abstract: Our results indicate that the functional status of DNA repair pathways determine the sensitivity of NSCLC cells to cisplatin. Direct targeting of the pathway that is involved in cisplatin resistance may be an effective strategy to surmount cisplatin resistance in NSCLC.

Cited by 41 publications

References 47 publications

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Weakening Impact of Excessive Human Serum Albumin (eHSA) on Cisplatin and Etoposide Anticancer Effect in C57BL/6 Mice with Tumor and in Human NSCLC A549 Cells

Knockdown of REV3 synergizes with ATR inhibition to promote apoptosis induced by cisplatin in lung cancer cells

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