Radiation-Induced DNA Damage and Repair in Cells of a Radiosensitive Human Malignant Glioma Cell Line

Allalunis-Turner, M. J.; Zia, P K; Barron, G.; Mirzayans, Razmik; Day, Rufus S.

doi:10.2307/3578948

Cited by 83 publications

(49 citation statements)

References 18 publications

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“…Indeed, an increased sensitivity to DNA DSB producing agents was reported previously for cells with mutant or inhibited DNA-PK activity. The human glioblastoma cell line MO59J, mutated in the DNA-PK CS gene, was highly sensitive to ionizing radiation (51). Increased radiosensitivity was observed in Ku70 (52) and Ku80 (53) knockout mice and in rodent cell lines with a decreased expression of the Ku80 gene (54).…”

Section: Discussionmentioning

confidence: 90%

Hypersensitivity of Tumor Cell Lines with Microsatellite Instability to DNA Double Strand Break Producing Chemotherapeutic Agent Bleomycin

Shagisultanova

Yamashita

et al. 2004

Cancer Research

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Genetic or epigenetic inactivation of DNA mismatch repair genes results in a strong mutator phenotype, known as the microsatellite mutator phenotype or microsatellite instability (MSI). This mutator phenotype causes mutations in genes responsible for the regulation of cell growth and survival/death and thus promotes the development and progression of tumors. In addition to such tumorigenic lesions, mutations in genes of other types of DNA repair, for example, DNA double-strand break (DNA DSB) repair, are found in tumor cells with MSI. We report here that the majority of MSI-positive tumor cell lines of different tissue origins (endometrial, ovarian, prostate, and colorectal carcinomas) are hypersensitive to bleomycin, a DNA DSB producing chemotherapeutic drug. We suggest that this hypersensitivity may be a result of inactivation of the DNA DSB repair activity by concomitant mutations of different DNA DSB repair genes. To provide experimental support to this hypothesis, we show that the subclones of the MSI-positive colorectal cancer cell line HCT-8 that bear heterozygous frameshift mutations in the DNA DSB repair gene DNA-PK CS are more sensitive to a combined treatment with bleomycin and the DNA protein kinase inhibitor LY294002 than the original HCT-8 cells, which are wild type for this gene. These results may be useful in designing therapies for MSI-positive cancer.

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Section: Discussionmentioning

confidence: 90%

Hypersensitivity of Tumor Cell Lines with Microsatellite Instability to DNA Double Strand Break Producing Chemotherapeutic Agent Bleomycin

Shagisultanova

Yamashita

et al. 2004

Cancer Research

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“…An important factor that governs tumor cell responsiveness to bleomycin is the cellular DNA DSB repair capacity, and, in line with this, increased sensitivity to bleomycin is observed in cells deficient in NHEJ (15,23,24). TFP, a phenothiazine class antipsychotic drug, has been reported to enhance bleomycin-induced cytotoxicity by a poorly characterized mechanism (2,4,5,22).…”

Section: Discussionmentioning

confidence: 99%

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

Polischouk¹,

Holgersson²,

Zong³

et al. 2007

Molecular Cancer Therapeutics

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Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non -small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycininduced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJmediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells. [Mol Cancer Ther 2007;6(8):2303 -9]

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“…U87MG is p53 wild-type whereas U138MG and LN-308 are p53 mutant (Wischhusen et al, 2003). M059K is DNA-PK wild type and M059J lack the p350 component of DNA-PK (Allalunis-Turner et al, 1995). All cell lines were cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum.…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Roos¹,

et al. 2006

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Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced glioma cell death is unknown. Here, we show that malignant glioma cells undergo apoptosis following treatment with the methylating agents N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined by colony formation and apoptosis following methylation is greatly stimulated by p53. Transfection experiments with O 6 -methylguanine-DNA methyltransferase (MGMT) and depletion of MGMT by O 6 -benzylguanine showed that, in gliomas, the apoptotic signal originates from O 6 -methylguanine (O 6 MeG) and that repair of O 6 MeG by MGMT prevents apoptosis. We further demonstrate that O 6 MeGtriggered apoptosis requires Fas/CD95/Apo-1 receptor activation in p53 non-mutated glioma cells, whereas in p53 mutated gliomas the same DNA lesion triggers the mitochondrial apoptotic pathway. This occurs less effectively via Bcl-2 degradation and caspase-9, -2, -7 and -3 activation. O 6 MeG-triggered apoptosis in gliomas is a late response (occurring >120 h after treatment) that requires extensive cell proliferation. Stimulation of cell cycle progression by the Pasteurella multocida toxin promoted apoptosis whereas serum starvation attenuated it. O 6 MeGinduced apoptosis in glioma cells was preceded by the formation of DNA double-strand breaks (DSBs), as measured by cH2AX formation. Glioma cells mutated in DNA-PK cs , which is involved in non-homologous endjoining, were more sensitive to TMZ-induced apoptosis, supporting the involvement of DSBs as a downstream apoptosis triggering lesion. Overall, the data demonstrate that cell death induced by TMZ in gliomas is due to apoptosis and that determinants of sensitivity of gliomas to TMZ are MGMT, p53, proliferation rate and DSB repair.

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Radiation-Induced DNA Damage and Repair in Cells of a Radiosensitive Human Malignant Glioma Cell Line

Cited by 83 publications

References 18 publications

Hypersensitivity of Tumor Cell Lines with Microsatellite Instability to DNA Double Strand Break Producing Chemotherapeutic Agent Bleomycin

Hypersensitivity of Tumor Cell Lines with Microsatellite Instability to DNA Double Strand Break Producing Chemotherapeutic Agent Bleomycin

The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non–small cell lung carcinoma cells to DNA double-strand break–induced cell death

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

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