Effect of DNA Repair Deficiencies on the Cytotoxicity of Drugs Used in Cancer Therapy - A Review

Calderón-Montaño, José Manuel; Burgos-Morón, Estefanía; Orta, Manuel Luís; López‐Lázaro, Miguel

doi:10.2174/0929867321666140601203816

Cited by 19 publications

(25 citation statements)

References 371 publications

(359 reference statements)

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“…[31][32][33][34][35] Abnormal expression of DNA repair factors is common in many forms of cancer and can have implications for patient prognosis and treatment. [36][37][38] Upregulation of certain repair proteins can decrease survival by increasing the risk of metastasis and causing resistance to certain forms of chemotherapy. [39][40][41] Down regulation of DNA repair proteins is a known risk factor for tumor formation.…”

Section: Introductionmentioning

confidence: 99%

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

Wang¹,

Stewart

Price³

2014

Cell Cycle

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Mammalian CST (CTC1-STN1-TEN1) is a telomere-associated complex that functions in telomere duplex replication and fill-in synthesis of the telomeric C-strand following telomerase action. CST also facilitates genome-wide replication recovery after HU-induced fork stalling by increasing origin firing. CTC1 and STN1 were originally isolated as a DNA polymerase a stimulatory factor. Here we explore how CST abundance affects recovery from drugs that cause different types of DNA damage and replication stress. We show that recovery from HU and aphidicolin induced replication stress is increased by CST over-expression. Elevated CST increases dNTP incorporation and origin firing after HU release and decreases the incidence of anaphase bridges and micronuclei after aphidicolin removal. While the frequency of origin firing after HU release is proportional to CST abundance, the number of cells entering S-phase to initiate replication is unchanged by CST overexpression or STN1 depletion. Instead the CST-related changes in origin firing take place in cells that were already in S-phase at the time of HU addition, indicating that CST modulates firing of late or dormant origins. CST abundance also influences cell viability after treatment with HU, aphidicolin, MMS and camptothecin. Viability is increased by elevated CST and decreased by STN1 depletion, indicating that endogenous CST levels are limiting. However, CST abundance does not affect viability after MMC treatment. Thus, CST facilitates recovery from many, but not all, forms of exogenous DNA damage. Overall our results suggest that CST is needed in stoichiometric amounts to facilitate re-initiation of DNA replication at repaired forks and/or dormant origins.

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Section: Introductionmentioning

confidence: 99%

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

Wang¹,

Stewart

Price³

2014

Cell Cycle

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“…These adducts are usually repaired by NER. Therefore, cells defective in NER are usually more sensitive to alkylating agents, including aziridine-containing drugs (18,19). We therefore evaluated the role of NER in the cytotoxic effect of AzGalp.…”

Section: Discussionmentioning

confidence: 99%

“…The hypersensitivity of NER-deficient cells to AzGalp may have therapeutic implications. Evidences suggest that tumor cells have defects in DNA repair pathways which make them incapable of correctly repairing some types of DNA lesions (18,24). These defects may explain why cancer cells are more sensitive than healthy cells to specific DNA-damaging drugs.…”

Section: Discussionmentioning

confidence: 99%

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<em></em><em>In Vitro</em> Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

Burgos-Morón¹,

N²,

Ml³

et al. 2018

Preprint

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We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (detected with the comet assay). Cells deficient in the DNA repair pathway nucleotide excision repair (NER) were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. The combinations of AzGalp with either oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also displayed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

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“…Excision repair cross-complementing 1 (ERCC1) plays a major role in the nucleotide excision repair pathway, and is required for the repair of DNA lesions, such as those induced by UV light or formed by electrophilic compounds like cisplatin (Calderón-Montaño et al, 2014). ERCC1 serves as an important DNA excision repair protein and is reported to be associated with tumor development (Goldstein and Kastan, 2015).…”

Section: Introductionmentioning

confidence: 99%

Effect of SNX-2112 on proliferation of esophageal cancer cells via regulation of excision repair cross-complementing 1, epidermal growth factor receptor, and p53 expression

Cy¹,

Ren²,

Yd³

2016

Genet. Mol. Res.

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ABSTRACT. SNX-2112 is a potential molecular targeted therapeutic drug against esophageal cancer (EC). However, its exact mechanism of action remains to be explained. The aim of this study was to investigate the effect of SNX-2112 on excision repair cross-complementing 1 (ERCC1), epidermal growth factor receptor (EGFR), and p53, to elucidate the mechanism of action of SNX-2112 on EC. Fresh tumor sections were surgically obtained from 65 patients with EC, and the expression of ERCC1, EGFR, and p53 was determined by immunohistochemical staining. Furthermore, the effect of SNX-2112 (0.2 µM) on the proliferation of EC-9706 cells and the expression of ERCC1, EGFR, and p53 in these cells were analyzed by a cell proliferation assay and western blot, respectively. We observed a significant decrease and increase in ERCC1 (P = 0.001) and p53 (P = 0.043) expression, respectively, and no significant difference in EGFR (P = 0.59) expression, with the TNM stage of EC, which suggested that ERCC1 and p53 could be potential markers for the TNM stage of EC. We also observed a significant increase in ERCC1 expression, and decrease in p53 and EGFR expression, in EC-9706 cells treated with SNX-2112 (P < 0.05), indicating the regulation of EC by SNX-2112. Furthermore, SNX-2112 treatment induced a significant decrease in the proliferation of EC-9706, which confirmed the function of SNX-2112. In summary, SNX-2112 inhibits the proliferation of EC cells by regulating the expression of ERCC1, EGFR, and p53.

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Effect of DNA Repair Deficiencies on the Cytotoxicity of Drugs Used in Cancer Therapy - A Review

Cited by 19 publications

References 371 publications

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

<em></em><em>In Vitro</em> Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

Effect of SNX-2112 on proliferation of esophageal cancer cells via regulation of excision repair cross-complementing 1, epidermal growth factor receptor, and p53 expression

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