DNA Synthesis and Cell Survival after X-irradiation of Mammalian Cells Treated with Caffeine or Adenine

Griffiths, Tony; Carpenter, J. G.; Dahle, Dan

doi:10.1080/09553007814550401

Cited by 32 publications

(3 citation statements)

References 24 publications

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“…As expected, in both cell lines radiation exposure inhibits ongoing DNA replication and ca eine reverses this e ect. The overshooting observed at low doses re¯ects the activation by ca eine of additional replication origins and has been previously described (Gri ths et al, 1978;Lehmann, 1972;Painter, 1980;Tatsumi and Strauss, 1979;Tolmach et al, 1977). For an evaluation of the e ect of ca eine Thus, despite the reduced ca eine radiosensitization to killing, cells defective in XRCC2 activate DNA damage checkpoints in S and G2 phases of the cell cycle, and ca eine e ectively disrupts this activation.…”

Section: Caffeine Abrogates Checkpoint Response In Cells Deficient Inmentioning

confidence: 99%

“…A widely held view is that radiosensitization derives from the ability of ca eine to disrupt multiple DNA damage-responsive cell cycle checkpoints. Indeed ca eine has been shown to reduce or eliminate p53 activation and G1-arrest (Kastan et al, 1991;Powell et al, 1995;Valenzuela et al, 2000), S phase delay (Gri ths et al, 1978;Murnane et al, 1980;Painter, 1980;Tolmach et al, 1977;Walters et al, 1974) and G2/M arrest (Jung and Stre er, 1992;Kimler et al, 1982;Lau and Pardee, 1982;Lucke-Huhle, 1982;Rowley, 1992;Tomasovic and Dewey, 1978) in cells exposed to ionizing radiation. Because checkpoints provide extra time that can be used for repair (Hartwell and Kastan, 1994;Hartwell and Weinert, 1989), abrogation by ca eine is expected to enhance the lethal and mutagenic e ects of DNA damaging agents.…”

Section: Introductionmentioning

confidence: 99%

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Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

et al. 2000

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The radiosensitizing e ect of ca eine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in ca eine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is a ected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays signi®cantly diminished ca eine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, ca eine e ectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not su cient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced ca eine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous endjoining (NHEJ) is radiosensitized by ca eine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly re¯ects NHEJ, remains una ected by ca eine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that ca eine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not su cient to explain radiosensitization. Indeed, immortalized ®bro-blasts from AT patients show ca eine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that ca eine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR. Oncogene (2000) 19, 5788 ± 5800.

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Section: Caffeine Abrogates Checkpoint Response In Cells Deficient Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

et al. 2000

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“…Indeed, caffeine has been shown to reduce or eliminate in irradiated cells p53 activation and G1 arrest (Kastan et al, 1991;Powell et al, 1995;Valenzuela et al, 2000), S-phase delay (Walters et al, 1974;Tolmach et al, 1977;Griffiths et al, 1978;Murnane et al, 1980;Painter, 1980) and G2/M arrest (Tomasovic and Dewey, 1978;Kimler et al, 1982;Lau and Pardee, 1982;Lu¨cke-Huhle et al, 1983;Jung and Streffer, 1992;Rowley, 1992), and the latter effect has been associated with increased apoptosis (Palayoor et al, 1995;Bernhard et al, 1996;Yao et al, 1996;Shinomiya et al, 1997). Numerous investigations, however, have failed to demonstrate a direct correlation between checkpoint abrogation and caffeine radiosensitization (Walters et al, 1974;Musk and Steel, 1990;Musk, 1991;Harvey and Savage, 1994;Ribeiro et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks

et al. 2004

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We recently reported that two Chinese hamster mutants deficient in the RAD51 paralogs XRCC2 and XRCC3 show reduced radiosensitization after treatment with caffeine, thus implicating homology-directed repair (HDR) of DNA double-strand breaks (DSBs) in the mechanism of caffeine radiosensitization. Here, we investigate directly the effect of caffeine on HDR initiated by DSBs induced by a rare cutting endonuclease (I-SceI) into one of two direct DNA repeats. The results demonstrate a strong inhibition by caffeine of HDR in wild-type cells, and a substantial reduction of this effect in HDR-deficient XRCC3 mutant cells. Inhibition of HDR and cell radiosensitization to killing shows similar dependence on caffeine concentration suggesting a cause-effect relationship between these effects. UCN-01, a kinase inhibitor that effectively abrogates checkpoint activation in irradiated cells, has only a small effect on HDR, indicating that similar to radiosensitization, inhibition of checkpoint signaling is not sufficient for HDR inhibition. Recombination events occurring during treatment with caffeine are characterized by rearrangements reminiscent to those previously reported for the XRCC3 mutant, and immunofluorescence microscopy demonstrates significantly reduced formation of IR-specific RAD51 foci after caffeine treatment. In summary, our results identify inhibition of HDR as a significant contributor to caffeine radiosensitization.

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Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice

1983

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A previous study demonstrated that caffeine strongly potentiated the teratogenic action of mitomycin C in mice. In the present study the effect of methylxanthines including caffeine, theophylline, theobromine (theobromine sodium salicylate), paraxanthine, and 1-methylxanthine was compared in order to analyze the structure-activity relationship. Jcl:ICR mice were injected IP with 3 mg/kg of mitomycin C, immediately followed by SC injection of each methylxanthine on day 11 of gestation. The doses of methylxanthines were calculated so that the mice received 50 mg/kg of caffeine or the equimolecular amount of the other methylxanthines. Fetuses were examined for external malformations on day 18 of gestation. Mitomycin C at 3 mg/kg and the methylxanthines at the doses used were not teratogenic. Combined administration of caffeine or theophylline with mitomycin C produced more than 80% of malformed fetuses. Although less effective than caffeine or theophylline, paraxanthine also significantly increased the incidence of malformed fetuses. Theobromine and 1-methylxanthine were virtually ineffective. From these findings, it is suggested that the methyl group at N-1 position of the xanthines is important for the enhancement but the N-1 methylation alone is ineffective unless accompanied with the substitution of the methyl moiety at the other position(s).

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DNA Synthesis and Cell Survival after X-irradiation of Mammalian Cells Treated with Caffeine or Adenine

Cited by 32 publications

References 24 publications

Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks

Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice

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