Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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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

  • Suh, Hyewon (Department of Pharmacy, College of Pharmacy, Hanyang University) ;
  • Choi, Ko-woon (Department of Pharmacy, College of Pharmacy, Hanyang University) ;
  • Lee, Chul-Hoon (Department of Pharmacy, College of Pharmacy, Hanyang University)
  • Received : 2014.12.30
  • Accepted : 2015.01.23
  • Published : 2015.03.28
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Abstract

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 $60{\mu}M$ 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 p21CIP1 showed that CR389 also induces p53-dependent-p21CIP1-mediated cell cycle arrest. Furthermore, apoptotic induction in $60{\mu}M$ 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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