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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. 2015. Mar, 25(3): 418-422
Copyright © 2015, The Korean Society For Microbiology And Biotechnology
  • Received : December 30, 2014
  • Accepted : January 23, 2015
  • Published : March 28, 2015
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About the Authors
Hyewon Suh
Ko-woon Choi
Chul-Hoon Lee
chhlee@hanyang.ac.kr

Abstract
In the course of screening for novel cell cycle inhibitors and apoptotic inducers, CR389, elucidated as 5-(1 H -benzoimidazol-2-yl)-1 H -pyridin-2-one, was generated as a new hit compound. Flow cytometric analysis and western blots of PA-1 cells treated with 40 µM 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 µM 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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Acknowledgements
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (2013R1A1A2011531).
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