scholarly journals 23-Hydroxyursolic Acid Isolated from the Stem Bark of Cussonia bancoensis Induces Apoptosis through Fas/Caspase-8-Dependent Pathway in HL-60 Human Promyelocytic Leukemia Cells

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3306 ◽  
Author(s):  
Jong-Heon Won ◽  
Kyung-Sook Chung ◽  
Eun-Young Park ◽  
Jeong-Hun Lee ◽  
Jung-Hye Choi ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Stem Bark ◽  
Promyelocytic Leukemia ◽  
Leukemia Cells ◽  
Caspase 8 ◽  
Signaling Complex ◽  
Induced Apoptosis ◽  
Apoptotic Effects

The natural product 23-hydroxyursolic acid (23-HUA) is a derivative of ursolic acid, which is known to induce cancer cell apoptosis. However, apoptotic effects and mechanisms of 23-HUA have not been well characterized yet. Herein, we investigated the molecular mechanisms of 23-HUA-induced apoptosis in HL-60 human promyelocytic leukemia cells. 23-HUA-treated HL-60 cells showed apoptotic features including internucleosomal DNA condensation and fragmentation as well as externalization of phosphatidylserine residues. 23-HUA induced a series of mitochondrial events including disruption of mitochondrial membrane potential (ΔΨm), cytochrome c and Smac/DIABLO release and loss of balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins in HL-60 cells. In addition, 23-HUA activated caspase-8, caspase-9 and caspase-3. Pretreatment with a broad caspase inhibitor (z-VAD-fmk), a caspase-3 inhibitor (z-DEVD-fmk), and a caspase-8 inhibitor (z-IETD-fmk) significantly attenuated 23-HUA-induced DNA fragmentation. After 23-HUA-induced apoptosis, proteins expression levels of FasL, Fas and FADD constituting the death-inducing signaling complex (DISC) were upregulated in HL-60 cells. Moreover, transfection with Fas or FADD siRNA significantly blocked 23-HUA-induced DNA fragmentation and caspases activation. Taken together, these findings indicate that 23-HUA induces apoptosis in HL-60 human promyelocytic leukemia cells through formation of DISC and caspase-8 activation leading to loss of ΔΨm and caspase-3 activation.

Berberine Induces Apoptotic Cell Death via Activation of Caspase-3 and -8 in HL-60 Human Leukemia Cells: Nuclear Localization and Structure–Activity Relationships

2017 ◽  
Vol 45 (07) ◽  
pp. 1497-1511 ◽  
Author(s):  
Shinya Okubo ◽  
Takuhiro Uto ◽  
Aya Goto ◽  
Hiroyuki Tanaka ◽  
Tsuyoshi Nishioku ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Antiproliferative Activity ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Leukemia Cells ◽  
Caspase 8 ◽  
Human Leukemia ◽  
Caspase 9

Berberine (BBR), an isoquinoline alkaloid, is a well-known bioactive compound contained in medicinal plants used in traditional and folk medicines. In this study, we investigated the subcellular localization and the apoptotic mechanisms of BBR were elucidated. First, we confirmed the incorporation of BBR into the cell visually. BBR showed antiproliferative activity and promptly localized to the nucleus from 5[Formula: see text]min to 15[Formula: see text]min after BBR treatment in HL-60 human promyelocytic leukemia cells. Next, we examined the antiproliferative activity of BBR (1) and its biosynthetically related compounds (2-7) in HL-60 cells. BBR exerted strongest antiproliferative activity among 1-7 and the results of structures and activity relation suggested that a methylenedioxyl group in ring A, an [Formula: see text]-alkyl group at C-9 position, and the frame of isoquinoline may be necessary for antiproliferative activity. Moreover, BBR showed the most potent antiproliferative activity in HL-60 cells among human cancer and normal cell lines tested. Next, we examined the effect of BBR on molecular events known as apoptosis induction. In HL-60 cells, BBR induced chromatin condensation and DNA fragmentation, and triggered the activation of PARP, caspase-3 and caspase-8 without the activation of caspase-9. BBR-induced DNA fragmentation was abolished by pretreatment with inhibitors against caspase-3 and caspase-8, but not against caspase-9. ERK and p38 were promptly phosphorylated after 15 min of BBR treatment, and this was correlated with time of localization to the nucleus of BBR. These results demonstrated that BBR translocated into nucleus immediately after treatments and induced apoptotic cell death by activation of caspase-3 and caspase-8.

CD44 Ligation Induces Apoptosis Via Caspase- and Serine Protease-Dependent Pathways in Acute Promyelocytic Leukemia Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4432-4432
Author(s):  
Eliane Maquarre ◽  
Cedric Artus ◽  
Zeineb Gadhoum ◽  
Claude Jasmin ◽  
Florence Smadja-Joffe ◽  
...  
Keyword(s):  
Serine Protease ◽  
Acute Promyelocytic Leukemia ◽  
Caspase 3 ◽  
Death Receptor ◽  
Promyelocytic Leukemia ◽  
Caspase 8 ◽  
Cytochrome C Release ◽  
Nb4 Cells ◽  
Effector Caspase ◽  
Induced Apoptosis

Abstract We have recently reported that ligation of the CD44 cell surface antigen with A3D8 monoclonal antibody (mAb) triggers incomplete differentiation and apoptosis of the acute promyelocytic leukemia (APL)-derived NB4 cells. The present study characterizes the mechanisms underlying the apoptotic effect of A3D8 in NB4 cells. We show that A3D8 induces activation of both initiator caspase -8 and -9, and effector caspase-3 and -7 but only inhibition of caspase-3/7 and caspase-8 reduces A3D8-induced apoptosis. Moreover, A3D8 induces mitochondrial alterations (decrease in mitochondrial membrane potential ΔΨm and cytochrome c release) which are reduced by caspase-8 inhibitor suggesting that caspase-8 is primarily involved in A3D8-induced apoptosis of NB4 cells. However, the apoptotic process is independent of TNF-family death receptor signalling. Interestingly, the general serine protease inhibitor 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) decreases A3D8-induced apoptosis and when combined with general caspase inhibitor displays an additive effect resulting in complete prevention of apoptosis. These results suggest that both caspase-dependent and serine protease-dependent pathways contribute to A3D8-induced apoptosis. Finally, A3D8 induces apoptosis in ATRA-resistant NB4-derived cells and in APL primary blasts, characterizing the A3D8 anti-CD44 mAb as a novel class of apoptosis-inducing agent in APL.

Hydroxypheophorbide-α-mediated photodynamic therapy augmented by pretreatment with genistein inCaSkicervical cancer cells

2009 ◽  
Vol 13 (07) ◽  
pp. 842-847
Author(s):  
Jang-In Shin ◽  
Jin-Chul Ahn ◽  
Sang-Joon Lee ◽  
Ock Jin Park ◽  
Phil-Sang Chung
Keyword(s):  
Photodynamic Therapy ◽  
Er Stress ◽  
Cancer Cells ◽  
Combination Treatment ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Red Light ◽  
Caspase 8 ◽  
Induced Apoptosis

Photodynamic therapy (PDT) is a treatment for cancer involving three key components — a sensitizing compound (light) tissue, and oxygen. In this study we applied phototreatment to cancer cells with 2 J.cm-2of red light after sensitizing with 9-hydroxypheophorbide-α (9-HpbD-α), a new chlorophyll-derived photosensitizer. We have investigated the cytotoxic and apoptotic effects of 9-HpbD-α-induced PDT in cervical cancer cells, the enhancing effect of genistein in PDT, and explored the molecular mechanisms of E6 or E7 oncogenes, apoptotic signaling molecules, and ER stress. Co-treatment downregulated the transcripts of the E6*I, E6*II, and E7 oncogenes. Combined treatment with PDT and genistein showed typical apoptotic features, i.e. apoptotic bodies. To elucidate the mechanism of combination treatment-induced apoptosis, various mediators of apoptosis were investigated. Activation of caspase-8, caspase-3, and PARP were distinct after combination treatment. Furthermore, ER stress-related proteins, such as CHOP and GRP78, were activated after combination treatment. We conclude that genistein sensitizes CaSki cells to apoptosis treated with PDT by 9-HpbD-α (0.59 μg/mL) through mechanisms that involve downregulation of the E6*I, E6*II, and E7 oncogenes, activation of caspase-8 or caspase-3, and ER stress.

A novel TNFR1-triggered apoptosis pathway mediated by class IA PI3Ks in neutrophils

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5953-5962 ◽  
Author(s):  
Barbara Geering ◽  
Ursina Gurzeler ◽  
Elena Federzoni ◽  
Thomas Kaufmann ◽  
Hans-Uwe Simon
Keyword(s):  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Caspase 8 ◽  
Tnf Receptor ◽  
Caspase Activation ◽  
Apoptosis Pathway ◽  
Tnf Α ◽  
Pi3k Activation ◽  
Amplification Loop ◽  
Induced Apoptosis

Abstract The most common form of neutrophil death is apoptosis. In the present study, we report surprising differences in the molecular mechanisms used for caspase activation between FAS/CD95-stimulated and TNF receptor 1 (TNFR1)–stimulated neutrophils. Whereas FAS-induced apoptosis was followed by caspase-8 activation and required Bid to initiate the mitochondrial amplification loop, TNF-α–induced apoptosis involved class IA PI3Ks, which were activated by MAPK p38. TNF-α–induced PI3K activation resulted in the generation of reactive oxygen species, which activated caspase-3, a mechanism that did not operate in neutrophils without active NADPH oxidase. We conclude that in neutrophils, proapoptotic pathways after TNFR1 stimulation are initiated by p38 and PI3K, but not by caspase-8, a finding that should be considered in anti-inflammatory drug-development strategies.

Molecular Characterization of PS-341 (bortezomib) Resistance: Implications for Overcoming Resistance Using Lysophosphatidic Acid Acyltransferase (LPAAT)-β Inhibitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2411-2411
Author(s):  
Teru Hideshima ◽  
Dharminder Chauhan ◽  
Kenji Ishitsuka ◽  
Noopur Raje ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Lysophosphatidic Acid ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Parp Cleavage ◽  
Migration And Invasion ◽  
Caspase 8 ◽  
M Cell ◽  
Tumor Cell Migration ◽  
Lysophosphatidic Acid Acyltransferase ◽  
Induced Apoptosis

Abstract PS-341 (bortezomib, Velcade™) is a promising novel agent for treatment of advanced multiple myeloma (MM); however, 65% of patients with relapsed refractory disease in a phase II study did not respond. Lysophosphatidic acid (LPA) is a phospholipid which mediates tumor cell migration and invasion. Recent studies have shown that inhibition of LPAAT-β inhibits both Ras/Raf/Erk and PI3K/Akt signaling cascades. We have previously shown that lysophosphatidic acid acyltransferase (LPAAT)-β inhibitor CT-32615 triggers caspase-dependent apoptosis, and can overcome resistance to conventional therapeutics (ie, dexamethasone, doxorubicin, melphalan) in MM cells. In this study, we determined whether CT-32615 could also overcome resistance to PS-341. We first characterized molecular mechanisms of resistance to PS-341 in DHL-4 lymphoma cells. DHL-4 cells express low levels of caspase-3 and caspase-8; furthermore, no cleavage in caspase-8, caspase-9, caspase-3, poly ADP-ribose polymerase (PARP), or DNA fragmentation factor (DFF) 45 is triggered by PS-341 treatment. We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH2-terminal kinase (JNK), which subsequently induces caspase-dependent apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis. Here we show that PS-341 does not induce phosphorylation of SEK-1, JNK, and c-Jun in DHL-4 cells, suggesting that it does not trigger a stress response. Importantly, CT-32615 inhibits growth of DHL-4 cells in a time- and dose-dependent fashion: a transient G2/M cell cycle arrest induced by CT-32615 is mediated via downregulation of cdc25c and cdc2. CT-32615 triggers swelling and cell membrane destruction in DHL-4 cells, without caspase/PARP cleavage or TUNEL-positivity, suggesting a necrotic response. Our studies therefore demonstrate that LPAAT-β inhibitor CT-32615 triggers necrosis even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.

scholarly journals Leptospira interrogans Induces Apoptosis in Macrophages via Caspase-8- and Caspase-3-Dependent Pathways

2008 ◽  
Vol 77 (2) ◽  
pp. 799-809 ◽  
Author(s):  
Dandan Jin ◽  
David M. Ojcius ◽  
Dexter Sun ◽  
Haiyan Dong ◽  
Yihui Luo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Host Cells ◽  
Caspase 8 ◽  
Lamin A ◽  
Leptospira Interrogans ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Caspase 6 ◽  
Induced Apoptosis

ABSTRACT Apoptosis of host cells plays an important role in modulating the pathogenesis of many infectious diseases. It has been reported that Leptospira interrogans, the causal agent of leptospirosis, induces apoptosis in macrophages and hepatocytes. However, the molecular mechanisms responsible for host cell death remained largely unknown. Here we demonstrate that L. interrogans induced apoptosis in a macrophage-like cell line, J774A.1, and primary murine macrophages in a time- and dose-dependent manner. Apoptosis was associated with the activation of cysteine aspartic acid-specific proteases (caspase-3, caspase-6, and caspase-8), the increased expression of Fas-associated death domain (FADD), and the cleavage of the caspase substrates poly(ADP-ribose) polymerase (PARP) and nuclear lamina protein (lamin A and lamin C). Caspase-9 was activated to a lesser extent, whereas no release of cytochrome c from mitochondria was detectable. Inhibition of caspase-8 impaired L. interrogans-induced caspase-3 and -6 activation, as well as PARP and lamin A/C cleavage and apoptosis, suggesting that apoptosis is initiated via caspase-8 activation. Furthermore, caspase-3 was required for the activation of caspase-6 and seemed to be involved in caspase-9 activation through a feedback amplification loop. These data indicate that L. interrogans-induced apoptosis in macrophages is mediated by caspase-3 and -6 activation through a FADD-caspase-8-dependent pathway, independently of mitochondrial cytochrome c-caspase-9-dependent signaling.

Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

2021 ◽  
Author(s):  
Kanchana Suksri ◽  
Namoiy Semprasert ◽  
Mutita Junking ◽  
Suchanoot Kutpruek ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Death Receptor ◽  
Caspase 8 ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

scholarly journals Phytic Acid Protects against 6-Hydroxydopamine-Induced Dopaminergic Neuron Apoptosis in Normal and Iron Excess Conditions in a Cell Culture Model

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Qi Xu ◽  
Anumantha G. Kanthasamy ◽  
Manju B. Reddy
Keyword(s):  
Dna Fragmentation ◽  
Phytic Acid ◽  
Caspase 3 ◽  
Fold Increase ◽  
Iron Chelator ◽  
Culture Model ◽  
A Cell ◽  
Induced Apoptosis ◽  
6 Hydroxydopamine ◽  
Stress Dependent

Iron may play an important role in Parkinson's disease (PD) since it can induce oxidative stress-dependent neurodegeneration. The objective of this study was to determine whether the iron chelator, phytic acid (IP6) can protect against 6-hydroxydopamine- (6-OHDA-) induced apoptosis in immortalized rat mesencephalic dopaminergic cells under normal and iron-excess conditions. Caspase-3 activity was increased about 6-fold after 6-OHDA treatment (compared to control; ) and 30 μmol/L IP6 pretreatment decreased it by 38% (). Similarly, a 63% protection () against 6-OHDA induced DNA fragmentation was observed with IP6 pretreatment. Under iron-excess condition, a 6-fold increase in caspase-3 activity () and a 42% increase in DNA fragmentation () with 6-OHDA treatment were decreased by 41% () and 27% (), respectively, with 30 μmol/L IP6. Together, our data suggest that IP6 protects against 6-OHDA-induced cell apoptosis in both normal and iron-excess conditions, and IP6 may offer neuroprotection in PD.

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