UCN-01 selectively enhances mitomycin C cytotoxicity in p53 defective cells which is mediated through S and/or G2 checkpoint abrogation

Sugiyama, Kazuyo; Shimizu, Makiko; Akiyama, Tadakazu; Tamaoki, Tatsuya; Yamaguchi, Ken; Takahashi, Rei; Eastman, Alan; Akinaga, Shiro

doi:10.1002/(sici)1097-0215(20000301)85:5<703::aid-ijc17>3.0.co;2-7

Cited by 80 publications

(45 citation statements)

References 8 publications

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“…The combination of UCN-01 and AG490 produced a synergistic inhibition in p53 mutant cell lines, based on the observation that the CI was substantially less than 1, whereas an antagonistic effect was observed in p53 wild type cell lines (data not shown). These results suggest that the potentiation of UCN-01 cytotoxicity by AG490 was selectively manifested in cells with defective p53 function, which resembles the results observed in other tumor types with combination of UCN-01 with cisdiamminedichloroplatinum (CDDP), camptothecin, mitomycin C, and irradiation [10,11,16,27].…”

Section: Combinatorial Efficacy Of Ag490 and Ucn-01 In Glioma Cell LIsupporting

confidence: 67%

AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

2007

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We determined the cytotoxicity of AG490 as a single agent and in combination with 7-OHhydroxystaurosporine (UCN-01) in a panel of malignant human glioma cell lines. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53-defective cells while sparing the normal cells. Cell proliferation was determined from dose-response curves. AG490 was effective as a cytotoxic agent alone regardless of p53 status. Combining the Chk1 inhibitor UCN-01 dramatically enhanced the response to AG490 in p53 mutated or deleted glioma cells. An opposite effect was noted in p53 wild-type cells, in which UCN-01 and AG490 had antagonist effects on cell proliferation and viability. We found that AG490 enhanced BAD phosphorylation in p53 wild type glioma cells, which appeared to protect against UCN-01 induced cytotoxicity, whereas AG490 enhances UCN-01-induced cytotoxicity in p53-defective cell lines by suppression of BAD phosphorylation, and induction of BAX and PARP cleavage. These observations highlight the potential for genotype-dependent factors to strongly influence response to signaling-targeted therapies in malignant gliomas and the importance of considering such factors in correlative response analyses for these agents.

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Section: Combinatorial Efficacy Of Ag490 and Ucn-01 In Glioma Cell LIsupporting

confidence: 67%

AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

2007

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“…Thus it appears, at least in colorectal tumour cell lines, that inhibition of the IR-induced G2 checkpoint is not necessarily associated with sensitisation to IR. This in contrast to other reports which have shown that UCN-01 is able to sensitise tumour cells to a range of DNA damaging agents, including IR (Akinaga et al, 1993;Bunch and Eastman, 1996;Wang et al, 1996;Shao et al, 1997;Sugiyama et al, 2000). There are other reported cases where abrogation of the G2 checkpoint is not always associated with sensitisation to DNA damage-induced apoptosis (Musk, 1991;Ribeiro et al, 1999) however in these cases the G2 checkpoint was overcome by caffeine.…”

Section: Experimental Therapeuticscontrasting

confidence: 57%

Abrogation of the radiation-induced G2 checkpoint by the staurosporine derivative UCN-01 is associated with radiosensitisation in a subset of colorectal tumour cell lines

et al. 2002

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Ionising radiation is commonly used in the treatment of colorectal cancer. Tumour cells with mutant p53 undergo cell cycle arrest at G2/M after ionising radiation and evidence suggests that abrogation of this G2 arrest can lead to a premature, aberrant mitosis, thus enhancing ionising radiation-induced cell killing. The G2 checkpoint inhibitor UCN-01 was thus investigated to determine whether it would abrogate the G2 checkpoint induced by 5 Gy ionising radiation in a range of colorectal tumour cell lines. Data presented show that, at doses that are alone non-toxic to the cells, UCN-01 inhibits the ionising radiation-induced G2 checkpoint in five colorectal tumour cell lines with mutant p53. The ability of UCN-01 to sensitise cells to ionising radiation-induced growth inhibition and apoptosis was also investigated and UCN-01 was found to radiosensitise two out of five cell lines. These results were confirmed by long-term colony forming efficiency studies. These results demonstrate that abrogation of the ionising radiation-induced G2 checkpoint is not necessarily associated with sensitisation to ionising radiation, however, some colorectal tumour cell lines can be radiosensitised by UCN-01. Although the mechanism of radiosensitisation is not clear, this may still be an important treatment strategy.

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“…The actions of Chk1 inhibitors in potentiating the toxicity of S phase DNAdamaging agents are likely independent of p53 status (Shao et al, 1997;Sugiyama et al, 2000;Eastman et al, 2002;Kohn et al, 2002), thus making them attractive for therapeutic uses. The exact extent of DNA damage caused by such mechanism-based combinations is unknown, but evidence supports the postulation that increases in apoptosis after checkpoint abrogation is caused by collapsing of replication forks.…”

Section: Checkpoint Dysregulationmentioning

confidence: 99%

Nucleoside analogs: molecular mechanisms signaling cell death

2008

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Nucleoside analogs are structurally similar antimetabolites that have a broad range of action and are clinically active in both solid tumors and hematological malignancies. Many of these agents are incorporated into DNA by polymerases during normal DNA synthesis, an action that blocks further extension of the nascent strand and causes stalling of replication forks. The molecular mechanisms that sense stalled replication forks activate cell cycle checkpoints and DNA repair processes, which may contribute to drug resistance. When replication forks are not stabilized by these molecules or when subsequent DNA repair processes are overwhelmed, apoptosis is initiated either by these same DNA damage sensors or by alternative mechanisms. Recently, strategies aimed at targeting DNA damage checkpoints or DNA repair processes have demonstrated effectiveness in sensitizing cells to nucleoside analogs, thus offering a means to elude drug resistance. In addition to their DNA synthesisdirected actions many nucleoside analogs trigger apoptosis by unique mechanisms, such as causing epigenetic modifications or by direct activation of the apoptosome. A review of the cellular and molecular responses to clinically relevant agents provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

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UCN-01 selectively enhances mitomycin C cytotoxicity in p53 defective cells which is mediated through S and/or G2 checkpoint abrogation

Cited by 80 publications

References 8 publications

AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

Abrogation of the radiation-induced G2 checkpoint by the staurosporine derivative UCN-01 is associated with radiosensitisation in a subset of colorectal tumour cell lines

Nucleoside analogs: molecular mechanisms signaling cell death

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