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Toxicol Appl Pharmacol. 2014 Jan 1;274(1):96-106. doi: 10.1016/j.taap.2013.10.021. Epub 2013 Nov 2.

Growth inhibitory effect of KYKZL-1 on Hep G2 cells via inhibition of AA metabolites and caspase-3 pathway and cell cycle arrest.

Author information

1
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
2
College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.
3
Department of Medicinal Chemistry, School of Pharmacy, Soochow University, Jiangsu, China.
4
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China; Department of Pharmacology, University of Michigan, Ann Arbor, USA. Electronic address: xudunlop@126.com.

Abstract

KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the inhibitory activity test on Hep G2 growth. We found that KYKZL-1 inhibited the growth of Hep G2 cells via inducing apoptosis. Further studies showed that KYKZL-1 activated caspase-3 through cytochrome c release from mitochondria and down regulation of Bcl-2/Bax ratio and reduced the high level of COX-2 and 5-LOX. As shown in its anti-inflammatory effect, KYKZL-1 also exhibited inhibitory effect on the PGE2 and LTB4 production in Hep G2 cells. Accordingly, exogenous addition of PGE2 or LTB4 reversed the decreases in cell viability. In addition, KYKZL-1 caused cell cycle arrest at the S-G2 checkpoint via the activation of p21(CIP1) protein and down-regulation of cyclin A expression. These data indicate that the growth inhibitory effect of KYKZL-1 is associated with inhibition of AA metabolites and caspase-3 pathway and cell cycle arrest. Combined with our previous findings, KYKZL-1 exhibiting COX/5-LOX inhibition may be a promising potential agent not only for inflammation control but also for cancer prevention/therapy with an enhanced gastric safety profile.

KEYWORDS:

COX; Caspase; Cell cycle arrest; Inflammatory mediators; LOX; NSAIDs

PMID:
24189224
DOI:
10.1016/j.taap.2013.10.021
[Indexed for MEDLINE]

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