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β-lapachone-Induced Apoptosis of Human Gastric Carcinoma AGS Cells Is Caspase-Dependent and Regulated by the PI3K/Akt Pathway  

Yu, Hai Yang (College of Natural Resources and Life Science, Dong-A University)
Kim, Sung Ok (Team for Scientification of Korean Medical Intervention (BK21 Plus) & Department of Herbal Pharmacology, College of Oriental Medicine, Daegu Haany University)
Jin, Cheng-Yun (School of Pharmaceutical Science, Zhengzhou University)
Kim, Gi-Young (Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University)
Kim, Wun-Jae (Department of Urology, Chungbuk National University College of Medicine)
Yoo, Young Hyun (Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center)
Choi, Yung Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine)
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Biomolecules & Therapeutics / v.22, no.3, 2014 , pp. 184-192 More about this Journal
${\beta}$-lapachone is a naturally occurring quinone that selectively induces apoptotic cell death in a variety of human cancer cells in vitro and in vivo; however, its mechanism of action needs to be further elaborated. In this study, we investigated the effects of ${\beta}$-lapachone on the induction of apoptosis in human gastric carcinoma AGS cells. ${\beta}$-lapachone significantly inhibited cellular proliferation, and some typical apoptotic characteristics such as chromatin condensation and an increase in the population of sub-G1 hypodiploid cells were observed in ${\beta}$-lapachone-treated AGS cells. Treatment with ${\beta}$-lapachone caused mitochondrial transmembrane potential dissipation, stimulated the mitochondria-mediated intrinsic apoptotic pathway, as indicated by caspase-9 activation, cytochrome c release, Bcl-2 downregulation and Bax upregulation, as well as death receptor-mediated extrinsic apoptotic pathway, as indicated by activation of caspase-8 and truncation of Bid. This process was accompanied by activation of caspase-3 and concomitant with cleavage of poly(ADP-ribose) polymerase. The general caspase inhibitor, z-VAD-fmk, significantly abolished ${\beta}$-lapachone-induced cell death and inhibited growth. Further analysis demonstrated that the induction of apoptosis by ${\beta}$-lapachone was accompanied by inactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. The PI3K inhibitor LY29004 significantly increased ${\beta}$-lapachone-induced apoptosis and growth inhibition. Taken together, these findings indicate that the apoptotic activity of ${\beta}$-lapachone is probably regulated by a caspase-dependent cascade through activation of both intrinsic and extrinsic signaling pathways, and that inhibition of the PI3K/Akt signaling may contribute to ${\beta}$-lapachone-mediated AGS cell growth inhibition and apoptosis induction.
${\beta}$-lapachone; Apoptosis; Caspase; PI3K/Akt;
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