title: β-lapachone-Induced Apoptosis of Human Gastric Carcinoma AGS Cells Is Caspase-Dependent and Regulated by the PI3K/Akt Pathway.
abstract: β-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 β-lapachone on the induction of apoptosis in human gastric carcinoma AGS cells. β-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 β-lapachone-treated AGS cells. Treatment with β-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 β-lapachone-induced cell death and inhibited growth. Further analysis demonstrated that the induction of apoptosis by β-lapachone was accompanied by inactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. The PI3K inhibitor LY29004 significantly increased β-lapachone-induced apoptosis and growth inhibition. Taken together, these findings indicate that the apoptotic activity of β-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 β-lapachone-mediated AGS cell growth inhibition and apoptosis induction.
authors.affiliation: College of Natural Resources and Life Science, Dong-A University, Busan 604-714.
authors.forename: Hai Yang
authors.initials: HY
authors.lastname: Yu
authors.affiliation: Team for Scientification of Korean Medical Intervention (BK21 Plus) & Department of Herbal Pharmacology, College of Oriental Medicine, Daegu Haany University, Daegu 706-828.
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Kim
authors.affiliation: School of Pharmaceutical Science, Zhengzhou University, Henan 450001, China.
authors.forename: Cheng-Yun
authors.initials: CY
authors.lastname: Jin
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690-756.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Department of Urology, Chungbuk National University College of Medicine, Cheongju 361-804.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602-714.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.affiliation: Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052 ; Anti-Aging Research Center & Blue-Bio Industry RIC, Dongeui University, Busan 614-714, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
keywords: Apoptosis; Caspase; PI3K/Akt; β-lapachone