title: Growth inhibitory effect of KYKZL-1 on Hep G2 cells via inhibition of AA metabolites and caspase-3 pathway and cell cycle arrest.
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.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Du
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Zhi-Yi
authors.initials: ZY
authors.lastname: Xiao
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Huan
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Zhu-Nan
authors.initials: ZN
authors.lastname: Gong
authors.affiliation: College of Chemistry and Materials Science, Nanjing Normal University, Nanjing, China.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Wei
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Shi-Qian
authors.initials: SQ
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xun
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Chang
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Meng-Yu
authors.initials: MY
authors.lastname: Xie
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Soochow University, Jiangsu, China.
authors.forename: Gui-Zhen
authors.initials: GZ
authors.lastname: Ao
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Qiu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Guang-Lin
authors.initials: GL
authors.lastname: Xu
mesh_terms: D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D010666:Phenylpropionates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D006131:Growth Inhibitors; C584310:KYKZL-1 compound; D010666:Phenylpropionates; D013267:Stilbenes; D016718:Arachidonic Acid; D053148:Caspase 3
keywords: COX; Caspase; Cell cycle arrest; Inflammatory mediators; LOX; NSAIDs