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• W1569696753 abstract "4911 Chk1 is a protein kinase that has been implicated as a key regulator of cell cycle progression and DNA repair. Inhibitors of chk1 (e.g., UCN-01) have been shown to selectively potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells, in some circumstances, and are under development as therapeutic agents. In this study, we examined the ability of PD-3218521, a new, small-molecule chk1 inhibitor with an in vitro IC50 of 5nM, to potentiate gemcitabine (Gem)-induced loss of clonogenicity in a panel of colorectal and pancreatic cancer cell lines. In most cell lines, 300 nM was the highest concentration of PD-321852 that was non-toxic when given by itself for 24 hr. When this “threshold” concentration of PD-321852 was combined with Gem in SW620 colorectal and BxPC3 pancreatic cancer cells, it enhanced clonogenic death by about 25-fold in each cell line, as compared to a 3-fold enhancement that was obtained with a comparable (threshold) concentration of UCN-01 (100 nM). Although UCN-01 and PD-321852 were each able to cause elevated levels of cdc25A protein, as expected following chk1 inhibition, this effect on cdc25A did not correlate with potentiation of cytotoxicity. For example, Panc-1 pancreatic cancer cells did demonstrate substantially elevated levels of cdc25A after chk1 inhibition, but were minimally sensitized to Gem by PD-321852 (less than 2-fold). Surprisingly, we observed that when PD-321852 was combined with Gem under conditions resulting in synergistic cytotoxicity, it caused a dramatic depletion of chk1 protein, as indicated by Western blot analysis. The loss of chk1 signal was mitigated by incubation with a proteasome inhibitor (LLnL), supporting the conclusion that it reflected a real decline in chk1 protein content, rather than a change in antibody reactivity. In contrast, only a slight loss of chk1 protein could be detected after treatment with UCN-01, and this required use of toxic concentrations of that agent. In addition, Panc-1 cells, which were minimally sensitized to Gem by PD-321852, were relatively resistant to the effects of PD-321852 on chk1 protein levels. Thus, it appeared to be the loss of chk1 protein, rather than the inhibition of chk1 and subsequent deregulation of cdc25A, that correlated with the synergistic effects of PD-321852 on Gem-induced cytotoxicity. We are currently investigating the mechanism(s) of PD-321852-mediated chk1 repression and the relationship between drug-induced loss of chk1 and potentiation of cytotoxicity. 1Palmer et al. 2004. Eur J Cancer Suppl 2:20." @default.
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• W1569696753 date "2006-04-15" @default.
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• W1569696753 title "The small-molecule chk1 inhibitor, PD-321852, causes synergistic depletion of chk1 protein and clonogenic death when combined with gemcitabine in colorectal and pancreatic tumor cells" @default.
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