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.

Decreased Poly(ADP-Ribose) Polymerase 1 Expression Attenuates Glucose Oxidase-Induced Damage in Rat Cochlear Marginal Strial Cells

“…There may be other mechanisms in addition to the typical caspase-dependent pathway that function in MCs. This notion is different from the conclusion drawn from a previous study suggesting that z-VAD-fmk could completely block the NGF/p75ngfr/ceramide-induced apoptosis of epithelial cells and neurons in otocysts and the cochleovestibular ganglia [46]. A more recent study found that z-VAD-fmk significantly reduced the number of annexin V-positive renal cancer cells and that this apoptosis was considered to be caspase-dependent [47].…”

β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers

“…Previous experiments have demonstrated that β-lap significantly inhibited cellular proliferation and induced apoptosis in human gastric carcinoma AGS cells via the activation of the PI3K/Akt pathway and thus providing a mechanism for the role of β-lap in cell survival 33 . Our results indicated that β-lap decreased the levels of the phosphorylations of the Akt, S6, and 4EBP1 proteins ( P  < 0.05) and increased the levels of phosphorylation of PTEN ( P  < 0.05), but had no significant effect on the total levels of these proteins ( P  > 0.05).…”

Mechanism of the inhibition of leukemia cell growth and induction of apoptosis through the activation of ATR and PTEN by the topoisomerase inhibitor 3EZ, 20Ac-ingenol

“…In contrast, transcription independent p53 apoptosis is mediated by interactions of mitochondrial p53 with Bcl-2 [46]. Although the class II catalytic inhibitors, ICRF-193 and merbarone, and the catalytic inhibitor of topoisomerase I, betulinic acid, are not known to induce apoptosis via Bcl-2 genes [20,22,32,39], the class I poison inhibitor of topoisomerase I, CPT and the catalytic inhibitor, ␤-lapachone, stimulates this mitochondrial apoptosis pathway [33,42,43]. In the present experiment, p53 upregulation was sustained for 24 h of exposure to 3EZ, 20Ac-ingenol, and Bax expression was elevated, Bcl-2 protein was downregulated, and caspase 3 was activated at this time point.…”

“…Moreover, the PI3K/Akt pathway response to DNA DSBs was induced by various chemotherapies, including CPT derivatives [29][30][31]. The topoisomerase I catalytic inhibitors, betulinic acid and ␤-lapachone, have also been studied extensively as cancer drugs, and although several studies reported that they induce PI3K/Akt inactivation [32,33], their ensuing apoptotic mechanisms remain unclear. We also reported previously that the catalytic topoisomerase I inhibitor 3EZ, 20Ac-ingenol induced DNA damage leading to apoptosis via Akt inactivation in B cell line, DT 40 [24].…”