title: CR389, a benzoimidazolyl pyridinone analog, induces cell cycle arrest and apoptosis via p53 activation in human ovarian cancer PA-1 cells.
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 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.
authors: Department of Pharmacy, College of Pharmacy, Hanyang University, Kyeonggi-do 426-791, Republic of Korea.
authors: Hyewon
authors: H
authors: Suh
authors: Ko-woon
authors: KW
authors: Choi
authors: Chul-Hoon
authors: CH
authors: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000628:therapy; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000604110:5-(1H-benzoimidazol-2-yl)-1H-pyridin-2-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D011728:Pyridones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases