The Action of Caffeine on X-Irradiated HeLa Cells. II. Synergistic Lethality

Busse, Paul M.; Bose, S. K.; Jones, R. W.; Tolmach, L. J.

doi:10.2307/3574634

Cited by 120 publications

(31 citation statements)

References 16 publications

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“…Expression of T alone in human diploid cells also induces increased chromosome damage and cell death (Ray et al, 1990). In addition, when mitotic delay following DNA damage is prevented by genetic mutations Hartwell, 1988, 1990;Brown et al, 1991;Weinert et al, 1994) or by chemical treatments (Busse et al, 1977(Busse et al, , 1978Lau and Pardee, 1982) that prematurely activate cyclin B/p34 cdc2 , cells su er signi®cantly more Disregulation of mitosis by SV40 T antigen T Hung-Tse Chang et al cytogenetic damage. It is also possible that aberrant mitotic events like improper spindle formation and mitotic nondisjunction (Levine et al, 1991;Fukasawa et al, 1996) may be incited by T antigen-induced disregulation of mitotic cell cycle kinases.…”

Section: Discussionmentioning

confidence: 99%

“…This delay of entry into mitosis is believed to facilitate the repair of damaged DNA prior to chromosome condensation and segregation, thereby preserving genomic integrity. When this mitotic checkpoint is abrogated by chemical agents (Busse et al, 1977(Busse et al, , 1978Lau and Pardee, 1982;Fan et al, 1995;Powell et al, 1995;Russell et al, 1995) and gene mutations (Weinert and Hartwell, 1988;Brown et al, 1991;Weinert et al, 1994;Walworth and Bernards, 1996), cells are sensitized to DNA damaging agents, often su ering dramatic increases in chromosome aberrations and cell killing.…”

Section: T Antigen Disrupts Three Mitotic Checkpoints Critical For Mamentioning

confidence: 99%

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Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Chang

Ray

et al. 1997

Oncogene

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SV40 large T antigen (T) inactivates the tumor suppressor proteins p53 and pRb, and can induce cells to enter DNA replication at inappropriate times. We show here that T also compromises three cell cycle checkpoints that regulate the entry into and exit from mitosis. Human diploid ®broblasts infected with a retrovirus expressing T displayed an attenuated radiation-induced mitotic delay, were more susceptible to chemical-induced uncoupling of mitosis from the completion of DNA replication, and were more likely to exit mitosis and rereplicate their DNA when mitotic spindle assembly was inhibited. Consistent with altered mitotic checkpoint control, cells expressing T displayed elevated protein levels and/or associated activities of the mitotic regulatory proteins cyclin A, cyclin B, Cdc25C and p34 cdc2 . These changes in mitotic control were evident within 5 ± 10 population doublings after retroviral infection, indicating a direct e ect of T expression. Cells acutely infected with the T-expressing retrovirus su ered numerical and structural chromosome aberrations, including increases in aneuploidy, dicentric chromosomes, chromatid exchanges and chromosome breaks and gaps. These ®ndings indicate that T rapidly disrupts mitotic checkpoints that help maintain genomic stability, and suggest mechanisms by which T induces chromosome aberrations and promotes the immortalization and neoplastic transformation of human cells.

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Section: Discussionmentioning

confidence: 99%

Section: T Antigen Disrupts Three Mitotic Checkpoints Critical For Mamentioning

confidence: 99%

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Chang

Ray

et al. 1997

Oncogene

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“…Caffeine is not a specific inhibitor of ATM and ATR, however, and many of its physiologic activities derive from its action on other enzymes, such as cyclic AMP phosphodiesterase [8]. Studies examining the effects of caffeine on cellular responses to DNA damage are motivated by reproducible demonstrations that it enhances the toxicity of radiations [9,10] and chemical carcinogens [11,12].…”

Section: Introductionmentioning

confidence: 99%

“…The concentration that inhibits ATM by 50% in vitro is 1 mM and the 50% inhibitory concentration for ATR is about 3 mM [1]. These concentrations define the range at which caffeine effectively reverses cell cycle checkpoints and enhances cytotoxicity in carcinogen-damaged cells [3,9,13] without significant toxicity of its own. Lower concentrations are less effective at reversing checkpoint function and higher concentrations cause a reduction in DNA synthesis associated with cytotoxicity [13].…”

Section: Introductionmentioning

confidence: 99%

“…For ionizing radiations (IR), caffeine produces maximal enhancement of cytotoxicity on late S/G2 cells [9], whereas for UVC maximal enhancement occurs in S [14]. These results are rationalized by the knowledge that DNA repair protects cells against the lethal effects of carcinogen-induced damage [15] and the expectation that reducing the time available for repair in proliferating cells reduces repair efficiency.…”

Section: Introductionmentioning

confidence: 99%

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Caffeine and human DNA metabolism: the magic and the mystery

Kaufmann

Heffernan

Beaulieu

et al. 2003

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The ability of caffeine to reverse cell cycle checkpoint function and enhance genotoxicity after DNA damage was examined in telomerase-expressing human fibroblasts. Caffeine reversed the ATM-dependent S and G2 checkpoint responses to DNA damage induced by ionizing radiation (IR), as well as the ATR-and Chk1-dependent S checkpoint response to ultraviolet radiation (UVC). Remarkably, under conditions in which IR-induced G2 delay was reversed by caffeine, IR-induced G1 arrest was not. Incubation in caffeine did not increase the percentage of cells entering the S phase 6-8 h after irradiation; ATM-dependent phosphorylation of p53 and transactivation of p21 Cip1/Waf1 post-IR were resistant to caffeine. Caffeine alone induced a concentration-and time-dependent inhibition of DNA synthesis. It inhibited the entry of human fibroblasts into S phase by 70-80% regardless of the presence or absence of wildtype ATM or p53. Caffeine also enhanced the inhibition of cell proliferation induced by UVC in XP variant fibroblasts. This effect was reversed by expression of DNA polymerase η, indicating that translesion synthesis of UVC-induced pyrimidine dimers by DNA pol η protects human fibroblasts against UVC genotoxic effects even when other DNA repair functions are compromised by caffeine.

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Cancer and the cell cycle

Ford

Pardee

1999

J. Cell. Biochem.

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The purpose of this short review is to provide an overview of mammalian somatic cell cycle events and their controls. Cell cycle-related studies have been under way for only 5% of this millennium, yet since then nearly 20,000 references have appeared. This vast literature cannot be detailed here, nor can fundamental information obtained with other organisms such as yeast and Xenopus, or topics such as the abbreviated cell cycle in early embryonic cells. (General references include Murray and Hunt [1993] The cell cycle, an introduction. New York: Oxford University Press, and Denhardt [1999] In: The molecular basis of cell cycle and growth control. p 225-304. New York: John Wiley & Sons, Inc.) J. Cell Biochem. Suppls. 32/33:166-172, 1999.

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The Action of Caffeine on X-Irradiated HeLa Cells. II. Synergistic Lethality

Cited by 120 publications

References 16 publications

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Caffeine and human DNA metabolism: the magic and the mystery

Cancer and the cell cycle

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