Repair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosis

Nyskohus, Laura S.; Watson, Amanda J.; Margison, Geoffrey P.; Leu, Richard K. Le; Kim, Susan W.; Lockett, Trevor; Head, Richard; Young, Graeme P.; Ying, Haoqiang

doi:10.1016/j.mrgentox.2013.10.001

Cited by 21 publications

(13 citation statements)

References 34 publications

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“…This faster DNA repair kinetics in the nucleus is consistent with studies measuring O 6 -MeG, an alkylating lesion which is completely repaired 48 hours after AOM treatment but it is not detected by the QPCR assay employed in our study (29). We speculate that this slower mtDNA damage kinetics could be due to a slower AOM distribution inside the mitochondria as compared to the nucleus.…”

Section: Discussionsupporting

confidence: 92%

Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer

Ballista-Hernández

Martínez-Ferrer

Vélez

et al. 2017

Molecular Cancer Research

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Changes in mitochondrial DNA (mtDNA) integrity have been reported in many cancers, however, the contribution of mtDNA integrity to tumorigenesis is not well understood. We used a transgenic mouse model that is haploinsufficient for the apurinic/apyrimidinic endonuclease 1 (Apex1+/-) gene, which encodes the base excision repair (BER) enzyme APE1, to determine its role in protecting mtDNA from the effects of azoxymethane (AOM), a carcinogen used to induce colorectal cancer (CRC). Repair kinetics of AOM-induced mtDNA damage was evaluated using quantitative PCR after a single AOM dose and a significant induction in mtDNA lesions in colonic crypts from both wild type (WT) and Apex1+/-animals were observed. However, Apex1+/- mice had slower repair kinetics in addition to decreased mtDNA abundance. Tumors were also induced using multiple AOM doses and both WT and Apex1+/-animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT and Apex1+/-animals, whereas a significant increase in nuclear DNA lesions was detected in tumors from Apex1+/- mice. Finally, tumors from Apex1+/-mice displayed an increased proliferative index and histological abnormalities. Taken together, these results demonstrate that APE1 is important for preventing changes in mtDNA integrity during AOM-induced CRC. Implications: Azoxymethane, a colorectal cancer carcinogen, generates damage to the mitochondrial genome and the BER enzyme APE1 is required to maintain its integrity.

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Section: Discussionsupporting

confidence: 92%

Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer

Ballista-Hernández

Martínez-Ferrer

Vélez

et al. 2017

Molecular Cancer Research

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“…Here we showed upregulation of Mgmt 24 h after DMH in wt rats. Given the suicidal mechanism of action of MGMT, our result is compatible with Nyskohus's findings [19] and suggests that the overexpression of the gene is due to a compensatory feedback mechanism. Although in DMH-treated Pirc rats the overexpression of Mgmt is not significant compared to that observed in DMH-treated wt rats, we document that the effect of DMH was present in both wt and Pirc rats, suggesting that the upregulation of Mgmt is a mechanism in common between the two genotypes.…”

Section: Discussionsupporting

confidence: 91%

“…Although Kerr and colleagues [16] showed downregulation of Mgmt expression in rat colon 6 h after azoxymethane (AOM), a metabolite of DMH acting on DNA with the same mechanism, several studies documented that Mgmt is upregulated by exposure to alkylating agents [11, 18]. Previous studies in rats also demonstrated that, shortly after AOM treatment, MGMT enzymatic activity is depleted and remains undetectable for two days [19]. Here we showed upregulation of Mgmt 24 h after DMH in wt rats.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profile of Colon Mucosa after Cytotoxic Insult in wt and Apc-Mutated Pirc Rats: Possible Relation to Resistance to Apoptosis during Carcinogenesis

Femia

Luceri

Lodovici

et al. 2016

BioMed Research International

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Apc-mutated Pirc rats, spontaneously developing intestinal tumours, are resistant to 1,2-dimethylhydrazine- (DMH-) induced colon apoptosis. To understand this phenomenon, we analyzed the expression of genotoxic stress-related genes Mgmt, Gsta1, and Gstp1 in the colon of wt and Pirc rats in basal conditions and 24 h after DMH; plasmatic oxidant/antioxidant status was also evaluated. After DMH, Mgmt expression was increased in both genotypes but significantly only in wt rats; Gsta1 expression was significantly increased in both genotypes. Gstp1 expression did not vary after DMH but was lower in Pirc rats. Moreover, for each genotype, we studied by microarray technique whole gene expression profile after DMH. By unsupervised cluster analysis, 28 genes were differentially modulated between the two genotypes. Among them were interferon-induced genes Irf7, Oas1a, Oasl2, and Isg15 and the transcription factor Taf6l, overexpressed in DMH-treated wt rats and unchanged in Pirc rats. RT-PCR confirmed their overexpression in DMH-treated wt rats and showed a slighter variation in DMH-treated Pirc rats. Taken together, despite a blunted induction of Irf7, Oas1a, and Mgmt, defective apoptosis in Pirc rats 24 h after DMH is not mirrored by major differences in gene expression compared with wt rats.

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“…In light of this, it is possible that the failure of TMZ to statistically improve mouse survival may have been secondary to kinetic considerations in that there was not enough cancer cell exposure to TMZ to exhaust the MGMT being produced over the time course of the model. Indeed, using a rat colon epithelium model, it has recently been shown that DNA methylation and subsequent alkylation by the TMZ-related compound, azoxymethane, triggers apoptosis only after the DNA repair enzyme, MGMT, is exhausted [39]. In our current model, the 96 h of in vitro TMZ exposure may not have been sufficient to sustain longterm exhaustion of MGMT activity by TMZ over the several months that the mouse model ran.…”

Section: Discussionmentioning

confidence: 84%

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

et al. 2015

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Glioblastoma multiforme (GBM) has nearly uniformly fatal with a median survival of less than 2 years. While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients. This pre-clinical study aimed to determine the potential clinical utility of VPA in the treatment of GBM. Primary GBM cells were treated with VPA as a monotherapy and in combination with temozolomide and irradiation. At clinically achievable concentrations, VPA was shown to be effective as a monotherapy agent in the five primary lines tested. VPA was then used as a sensitizing agent to in vitro radiation and showed significant augmentation of in vitro irradiation therapy. In addition, when VPA, radiation and temozolomide were combined an additive, rather than synergistic effect was noted. Gene expression profiling demonstrated close clustering of triple treated cells with VPA mono-treated cells while untreated cells clustered closer with TMZ-irradiation dual treated cells. These microarray data suggest a dominant role of VPA at the gene expression level when combining these different treatment options. Moreover, in an in vivo tumor transplantation model, we were able to demonstrate an increase in animal survival when cells were pre-treated with irradiation-VPA and when triple treated. These findings provide a significant rationale for the investigation of VPA in the treatment of GBM patients.

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Repair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosis

Cited by 21 publications

References 34 publications

Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer

Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer

Gene Expression Profile of Colon Mucosa after Cytotoxic Insult in wt and Apc-Mutated Pirc Rats: Possible Relation to Resistance to Apoptosis during Carcinogenesis

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

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