• BMB Reports
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• v.35 no.1
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• pp.24-27
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• 2002

Apoptotic cell death is an active process mediated by various signaling pathways, which include the caspase cascade and the stress-activated protein kinase pathways. The caspase cascade is activated by two distinct routes: one from cell surface and the other from mitochondria. Activation of the route from cell surface requires the cellular components that include membrane receptors, adaptor proteins such as TRADD and FADD, and caspase-8, while activation of the other from mitochondria requires Apaf-1, caspase-9, and cytosolic cytochrome c. On the other hand, persistent stimulation of the stress-activated protein kinase pathway is also shown to mediate apoptosis in many cell types. Gene-targeting studies with jnk- or jip-null mice, in particular, strongly suggest that this signaling pathway plays a pivotal role in the cellular machinery for apoptosis.

• Journal of Integrative Natural Science
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• v.7 no.4
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• pp.227-233
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• 2014

Caspases, a family of cysteinyl aspartate-specific proteases plays a central role in the regulation and the execution of apoptotic cell death. Activation of caspases-3 stimulates a signaling pathway that ultimately leads to the death of the cell. Hence, caspase-3 has been proven to be an effective target for reducing the amount of cellular and tissue damage. In this work, comparative molecular similarity indices analysis (CoMSIA) was performed on a series of 3,4-dihydropyrimidoindolones derivatives which are inhibitors of caspase-3. The best predictions were obtained for CoMSIA model ($q^2$ = 0.586, $r^2$ = 0.955). The predictive ability of test set ($r^2_{pred}$) was 0.723. Statistical parameters from the generated QSAR models indicated the data is well fitted and have high predictive ability. Our theoretical results could be useful to design novel and more potent caspase-3 derivatives.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.167.1-167.1
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• 2003

Here we show that panaxadiol, a ginseng saponin with a dammarane skeleton, induces acute apoptotic cell death in human hepatoma SK-HEP-1 cells as evidenced by analysis of DNA fragmentation, caspase activation, and changes in cell morphology. The kinetic study showed that panaxadiol-induced apoptosis is associated with depolarization of mitochondrial membrane potential and cytochrome c release. Sequential activations of caspases-depolarization of mitochondrial membrane potential and cytochrome c release. Sequential activations of caspases-9, and -3, or -7, but not of caspase 8 coincide well in a time dependent manner with mitochondrial membrane depolarization and cytochrome c release from mitochondria during apoptosis of SK-HEP-1 cells induced by treatment with panaxadiol. (omitted)

• Archives of Pharmacal Research
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• v.23 no.1
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• pp.1-16
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• 2000

Many natural products elicit diverse pharmacological effects. Using two classes of potential chemopreventive compounds, the phenolic compounds and the isothiocyanates, we review the potential utility of two signaling events, the mitogen-activated protein kinases (MAPKs) and the ICE/Ced-3 proteases (caspases) stimulated by these agents in mammalian cell lines. Studies with phenolic antioxidants (BHA, tBHQ), and natural products (flavonoids; EGCG, ECG, and isothiocyanates; PEITC, sulforaphane), provided important insights into the signaling pathways induced by these compounds. At low concentrations, these chemicals may activate the MAPK (ERK2, JNK1, p38) leading to gene expression of survival genes (c-Fos, c-Jun) and defensive genes (Phase II detoxifying enzymes; GST, QR) resulting in survival and protective mechanisms (homeostasis response). Increasing the concentrations of these compounds will additionally activate the caspase pathway, leading to apoptosis (potential cytotoxicity). Further increment to suprapharmacological concentrations will lead to nonspecific necrotic cell death. The wider and narrow concentration ranges between the activation of MAPK/gene induction and caspases/cell death exhibited by phenolic compounds and isothiocyanates, respectively, in mammalian cells, may reflect their respective therapeutic windows in vivo. Consequently, the studies of signaling pathways elicited by natural products will advance our understanding of their efficacy and safety, of which many man become important therapeuitc drugs of the future.

• Korean Journal of Pharmacognosy
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• v.40 no.1
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• pp.65-69
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• 2009

The present study investigated the antiproliferative effect of Litsea japonica in HL-60/ADR, adriamycin resistant human promyelocytic leukemia cells. The 80% ethanol extract of L. japonica markedly inhibited the growth of HL-60/ADR cells. When HL-60/ADR cells were treated with the extract, several apoptosis events like as DNA fragmentation, chromatin condensation and the increase of the population of sub-G1 hypodiploid cells were observed. In the mechanism of apoptosis induction by L. japonica, we examined the changes of Bcl-2 and Bax protein expression levels, and activation of caspases. After the HL-60/ADR cells were treated with the extract, the Bcl-2 expression was decreased, whereas the expression of Bax was increased in a time-dependent manner compared to the control. In addition, the active forms of caspase-9 and -3 were increased and the cleavage of poly (ADP-ribose) polymerase, a vital substrate of effector caspase, was observed. The results suggest that the inhibitory effect of L. japonica on the growth of the HL-60/ADR appears to arise from the induction of apoptosis via the down-regulation of Bcl-2 and the activation of caspases.

• Journal of Microbiology and Biotechnology
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• v.21 no.9
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• pp.903-913
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• 2011

Vibrio parahaemolyticus, which causes gastroenteritis, wound infection, and septicemia, has two sets of type III secretion systems (TTSS), TTSS1 and TTSS2. A TTSS1-deficient vcrD1 mutant of V. parahaemolyticus showed an attenuated cytotoxicity against HEp-2 cells, and a significant reduction in mouse lethality, which were both restored by complementation with the intact vcrD1 gene. V. parahaemolyticus also triggered phosphorylation of mitogen-activated protein kinases (MAPKs) including p38 and ERK1/2 in HEp-2 cells. The ability to activate p38 and ERK1/2 was significantly affected in a TTSS1-deficient vcrD1 mutant. Experiments using MAPK inhibitors showed that p38 and ERK1/2 MAPKs are involved in V. parahaemolyticus-induced death of HEp-2 cells. In addition, caspase-3 and caspase-9 were processed into active forms in V. parahaemolyticus-exposed HEp-2 cells, but activation of caspases was not essential for V. parahaemolyticus-induced death of HEp-2 cells, as shown by both annexin V staining and lactate dehydrogenase release assays. We conclude that secreted protein(s) of TTSS1 play an important role in activation of p38 and ERK1/2 in HEp-2 cells that eventually leads to cell death via a caspase-independent mechanism.

• Journal of Cancer Prevention
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• v.23 no.4
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• pp.170-175
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• 2018

Background: Human hepatocellular carcinoma (HCC) is a common liver tumor and the main cause of cancer-related death. Tyrosine kinase inhibitors, such as imatinib and GNF5 which were developed to treat chronic myelogenous leukemia, regulate the progression of various cancers. The aim of this study was to confirm the anti-tumor activity of tyrosine kinase inhibitors through regulation of S-phase kinase-associated protein 2 (Skp2), an important oncogenic factor in various cancer cells, in human hepatocarcinoma SK-HEP1 cells. Methods: Cell viability and colony formation assays were conducted to evaluate the effects of imatinib, GNF5 and GNF2 on the growth of SK-HEP1 cells. Using immunoblot analysis, we assessed change of the activation of caspases, PARP, Akt, mitogen-activated protein kinases, and Skp2/p27/p21 pathway by imatinib and GNF5 in SK-HEP1 cells. Using sh-Skp2 HCC cells, the role of Skp2 in the effects of imatinib and GNF5 was evaluated. Results: Imatinib and GNF5 significantly inhibited the growth of SK-HEP1 cells. Treatment of imatinib and GNF5 decreased Skp2 expression and Akt phosphorylation, and increased the expression of p27, p21, and active-caspases in SK-HEP1 cells. In sh-Skp2 HCC cells, cell growth and the expression of Skp2 were inhibited by more than in the mock group treated with imatinib and GNF5. Conclusions: These results suggest that the anti-growth activity of tyrosine kinase inhibitors may be associated with the regulation of p27/p21 and caspases through Skp2 blockage in HCC cells.

• Herbal Formula Science
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• v.14 no.2
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• pp.21-32
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• 2006

The purpose of this study was to investigate the effect of Imyosan on apoptosis in human colorectal cancer HCT116 cells. Phellodendron amurense Rupr. and Atratylodes lancea D.C. compose Imyosan. First of all, to study the cytotoxic effect of methanol extract of Imyosan (IMS-MeOH) on HCT116 cells, the cells were treated with various concentrations of IMS-MeOH and then cell viability was determined by XTT reduction method. IMS-MeOH reduced viability of HCT116 cells in a dose and time-dependent manner. To confirm the induction of apoptosis, the c1eavage of poly ADP-ribose polymerase (PARP), a substrate for caspase-3 and a typical sign of apoptosis, and the activation of caspase-3, procaspase-8 and procaspase-9 were examined by western blot analysis. IMS-MeOH decreased procaspase-3, procaspase-8 and procaspase-9 levels in a dose-dependent manner and induced the clevage of PARP. IMS-MeOH triggered the mitochondrial apoptotic signaling by increasing the release of cytochrome c from mitochondria to cytosol. Furthermore, IMS-MeOH also downregulated the anti-apoptotic Bcl-2 and upregulated the pro-apoptotic-Bax. Therefore, these results suggest that IMS-MeOH induced HCT1l6 cell death through the mitochondrial pathway. To explore whether the activities of caspases was required for induction of apoptosis by IMS-MeOH, caspase-3, -8, -9 activity measured by using substrates, respectively. IMS-MeOH increased caspase-3, -8, -9 activity. Co-treatment with inhibitors of caspase-3, -8, -9 and IMS-MeOH significantly blocked IMS-MeOH-triggered apoptosis in HCT1l6 cells. These results suggest that IMS-MeOH induces caspases-mediated apoptosis.

• Journal of Microbiology and Biotechnology
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• v.19 no.11
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• pp.1355-1363
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• 2009

In the present study, the neuroprotective effects of astaxanthin on $H_2O_2$-mediated apoptotic cell death, using cultured mouse neural progenitor cells (mNPCs), were investigated. To cause apoptotic cell death, mNPCs were pretreated with astaxanthin for 8 h and followed by treatment of 0.3 mM $H_2O_2$. Pretreatment of mNPCs with astaxanthin significantly inhibited $H_2O_2$-mediated apoptosis and induced cell growth in a dose-dependent manner. In Western blot analysis, astaxanthin-pretreated cells showed the activation of p-Akt, p-MEK, p-ERK, and Bcl-2, and the reduction of p-P38, p-SAPK/JNK, Bax, p-GSK3b, cytochrome c, caspase-3, and PARP. Because $H_2O_2$ triggers caspases activation, this study examined whether astaxanthin can inhibit caspases activation in $H_2O_2$-treated mNPCs. After $H_2O_2$ treatment, caspases activities were prominently increased, but astaxanthin pretreatment significantly inhibited $H_2O_2$-mediated caspases activation. Astaxanthin pretreatment also significantly recovered the ATP production ability of $H_2O_2$-treated cells. These findings indicate that astaxanthin inhibits $H_2O_2$-mediated apoptotic features in mNPCs. Inhibition assays with SB203580 ($10\;{\mu}M$, a specific inhibitor of p38) and PD98059 ($10\;{\mu}M$, a specific inhibitor of MEK) clearly showed that astaxanthin can inhibit $H_2O_2$-mediated apoptotic death via modulation of p38 and MEK signaling pathways.

• The Korea Journal of Herbology
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• v.22 no.2
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• pp.65-72
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• 2007

Objectives : In this study, we investigate that Euphorbiae lathyridis Semen extract contributes to growth inhibitory effect and anti-cancer activity on the HT-29 human colon cancer cells. Methods : Euphorbiae lathyridis Semen was extracted from the Semen of the plant using 80% Methanol. The Euphorbiae lathyridis Semen extract was treated to different concentrations for 24 hr, 4Shr or 72hr. Growth inhibitory effect was analyzed by measuring FACS study and MTT assay. Cell apoptosis was confirmed by surveying caspases cascades activation using Westem blot. Results : Exposure to Euphorbiae lathyridis Semen extract (0.4mg/ml) results in an inhibitory effect on cell growth in HT-29 cells. Growth inhibition by Euphorbiae lathyridis Semen extract in HT-29 cells was related with the inhibition of proliferation and induction of apoptosis. The Euphorbiae lathyridis Semen extract induces DNA fragmentation in HT-29 cells. Furthermore, Euphorbiae lathyridis Semen extract induces cell apoptosis through the activation of caspases-3, caspase-9 and PARP cleavage. Conclusion : Euphorbiae lathyridis Semen extract induces apoptosis in human colon cancer cells, therefore, we suggest that Euphorbiae lathyridis Semen extract can be used as a novel class of anti-cancer drugs.