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CR389, a benzoimidazolyl pyridinone analog, induces cell cycle arrest and apoptosis via p53 activation in human ovarian cancer PA-1 cells



CR389, a benzoimidazolyl pyridinone analog, induces cell cycle arrest and apoptosis via p53 activation in human ovarian cancer PA-1 cells



Journal of Microbiology and Biotechnology 25(3): 418-422



In the course of screening for novel cell cycle inhibitors and apoptotic inducers, CR389, elucidated as 5-(1H-benzoimidazol-2-yl)-1H-pyridin-2-one, was generated as a new hit compound. Flow cytometric analysis and western blots of PA-1 cells treated with 40 micrometer CR389 revealed an appreciable cell cycle arrest at the G2/M phase through direct inhibition of the CDK1 complex. In addition, activation of p53 via phosphorylation at Ser15 and subsequent up-regulation of p21(CIP1) showed that CR389 also induces p53-dependent-p21(CIP1)-mediated cell cycle arrest. Furthermore, apoptotic induction in 40 micrometer CR389-treated PA-1 cells is associated with the release of cytochrome c from mitochondria through up-regulation of the proapoptotic Bax protein, which results in the activation of procaspase-9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). Accordingly, CR389 seems to have multiple mechanisms of antiproliferative activity through p53-mediated pathways against human ovarian cancer cells. Therefore, we conclude that CR389 is a candidate therapeutic agent for the treatment of human ovarian cancer via the activation of p53.

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Accession: 057338867

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PMID: 25639717


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