scholarly journals Adriamycin activity's durational governance of different cell death types and zonality in rat liver acinus. Immunohistochemical studies

2014 ◽  
Vol 58 (1) ◽  
pp. 125-133
Author(s):  
Agnieszka Pedrycz ◽  
Zbigniew Boratyński ◽  
Piotr Siermontowski ◽  
Jacek Mendocha ◽  
Marcin Orłowski ◽  
...  
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Mitochondrial Pathway ◽  
Immunohistochemical Method ◽  
Extrinsic Pathway ◽  
Apoptotic Pathway ◽  
Liver Acinus ◽  
Group I ◽  
Female Wistar Rats ◽  
Immunohistochemical Studies

Abstract The aim of this study was to develop and examine a model of apoptosis and necrosis of hepatocytes induced by a damaging factor - adriamycin, correlating time after its administration with cell death type, and to investigate the localisation within the liver acinus of hepatocytes dying in these two ways. The results obtained in the present and previous studies were compared in order to make a map of cell death localisation in the liver acinus, showing the effect of time in action and dose of adriamycin. The experiment was performed on 32 female Wistar rats, divided into four groups: I and II - experimental, and III and IV - control. Adriamycin (3 mg/kg b.w.) was administered intraperitoneally to rats in groups I and II, and the rats were decapitated after four (group I) and eight (group II) weeks. Animals in control groups III and IV were given 0.5 mL of 0.9% NaCl solution, and decapitated after four and eight weeks respectively. Sections of the liver were examined with a three-stage immunohistochemical method. This method allowed to examine hepatocytes qualitatively and quantitatively for the presence of proteins involved in three types of apoptosis: induced by the mitochondrial pathway (caspase 3, 9), the intrinsic pathway related to endoplasmic reticulum stress (caspase 3, 12), and the extrinsic pathway (caspase 3, 8). One of the inflammatory markers, caspase 1, was also examined. The zonal localisation of all three types of apoptosis was assessed in the liver tissue. More oxidated hepatocytes indicated only signs of the internal mitochondrial pathway, whereas less oxidated hepatocytes induced the internal reticular pathway and the external apoptotic pathway. The period between adriamycin administration and hepatic cell investigation was a main factor of the process. A longer period post insult resulted in a more pronounced effect of the activation of apoptosis. Sections explored eight weeks after treatment with different doses of the drug (3 and 5 mg/kg in the previous study) showed a similar intensity of apoptosis.

scholarly journals Characterization of cell-death pathways in Punta Toro virus-induced hepatocyte injury

2008 ◽  
Vol 89 (9) ◽  
pp. 2175-2181 ◽  
Author(s):  
Fangling Xu ◽  
Xiaodong Liang ◽  
Robert B. Tesh ◽  
Shu-Yuan Xiao
Keyword(s):  
Cell Death ◽  
Hepg2 Cells ◽  
Antigen Expression ◽  
Mitochondrial Pathway ◽  
Cellular Viability ◽  
Tnf Receptor ◽  
Extrinsic Pathway ◽  
Punta Toro Virus

Punta Toro virus (PTV; genus Phlebovirus, family Bunyaviridae) causes apoptosis of hepatocytes in vivo in experimentally infected hamsters and in vitro in cultured HepG2 cells. Screening for expression of apoptosis-related genes has shown alterations in the genes for tumour necrosis factor-α (TNF-α) and the TNF receptor family. This study examined the roles of the TNF receptor-related extrinsic pathway and the Bcl-2 family-associated mitochondrial pathway in PTV-induced cell death. The effects of caspase inhibitors (caspIs) and TNF on cellular viability, virus replication, and morphological and biochemical changes in apoptosis were examined in HepG2 cells at different time points after infection with PTV (Adames strain). The results showed that caspIs dampened the virus-induced reduction in cellular viability, partially suppressed and delayed viral titres and antigen expression, and partially decreased the expression of apoptotic genes, caspase activities and DNA fragmentation. TNF treatment further decreased cellular viability after PTV infection and increased the level of apoptosis, whilst caspIs partially inhibited these effects. These findings indicate that TNF, caspase-8 and caspase-9 contribute to PTV-induced hepatocytic apoptosis and that additional mediators are probably also involved in this process. These mediators from different pathways correlated with one another and may be interlinked.

scholarly journals Pomegranate Juice Induced Cell Cycle Arrest and Apoptosis Via Mitochondrial Pathway in Human Lung Aden carcinoma A549 Cells

2018 ◽  
Vol 7 (3.21) ◽  
pp. 287
Author(s):  
Radiah Abdul Ghani ◽  
Nik Nurasyikin Nik Abdul Malek ◽  
Noor Suryani Mohd Ashari ◽  
Norzamzila Abdullah
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
A549 Cells ◽  
Mitochondrial Pathway ◽  
Pomegranate Juice ◽  
Mitochondrial Membrane Permeability ◽  
Cycle Arrest

Lung cancer is the most common type of cancer which the mortality rate increases year by year. Therapeutic drugs could not control the progression of cancer and it contributes to the side effects in normal cells. Thus, an alternative strategy using natural product becomes a focus today. Punica granatum, known as pomegranate  has demonstrated the anti-proliferative effect in A549 cells. To further confirm its efficacy, this study aimed to investigate the type of cell death and its pathway in A549 cells. Propium Iodide staining was applied to determine the cell cycle profile changes induced by this juice. The determination of type of cell death was done using Annex in-V staining and later will be analyzed using flow cytometer. The pathway to apoptosis was investigated by determining the caspase- 3, 8 and 9 activities. The findings were supported by mitochondrial membrane permeability assay and cytochrome c release detection which were later analyzed using flow cytometer. This study revealed that pomegranate juice induced cell cycle arrest at G0/G1 phase and apoptosis through intrinsic pathway following 24 h treatment. Pomegranate juice caused loss of mitochondrial membrane permeability after 48 h (p<0.05) exposure and a release of cytochrome c in cytosol after 24 h (p<0.05) and 48 h (p<0.01) exposure in treated A549 cells. In caspases analysis, it was showed that there was activation of caspase-3 following 72 h (p<0.01) treatment and caspase-9 after 48 (p<0.01) and 72 h (p<0.05) exposure in treated A549 cells. It can be concluded that pomegranate juice able to cause A549 cell growth inhibition by inducing cell cycle arrest and apoptosis through mitochondrial pathway. 

scholarly journals Diosgenin Induces Apoptosis in HepG2 Cells through Generation of Reactive Oxygen Species and Mitochondrial Pathway

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Dae Sung Kim ◽  
Byoung Kook Jeon ◽  
Young Eun Lee ◽  
Won Hong Woo ◽  
Yeun Ja Mun
Keyword(s):  
P38 Mapk ◽  
Hepg2 Cells ◽  
Caspase 3 ◽  
Mitochondrial Pathway ◽  
Carcinoma Cells ◽  
Dapi Staining ◽  
Apoptotic Pathway ◽  
Induced Apoptosis ◽  
Dose Dependent ◽  
Human Hepatocellular Carcinoma Cells

Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a precursor of various synthetic steroidal drugs. Diosgenin is studied for the mechanism of its action in apoptotic pathway in human hepatocellular carcinoma cells. Based on DAPI staining, diosgenin-treated cells manifested nuclear shrinkage, condensation, and fragmentation. Treatment of HepG2 cells with 40 μM diosgenin resulted in activation of the caspase-3, -8, -9 and cleavage of poly-ADP-ribose polymerase (PARP) and the release of cytochromec.In the upstream, diosgenin increased the expression of Bax, decreased the expression of Bid and Bcl-2, and augmented the Bax/Bcl-2 ratio. Diosgenin-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of JNK, p38 MAPK and apoptosis signal-regulating kinase (ASK)-1, as well as generation of the ROS. NAC administration, a scavenger of ROS, reversed diosgene-induced cell death. These results suggest that diosgenin-induced apoptosis in HepG2 cells through Bcl-2 protein family-mediated mitochndria/caspase-3-dependent pathway. Also, diosgenin strongly generated ROS and this oxidative stress might induce apoptosis through activation of ASK1, which are critical upstream signals for JNK/p38 MAPK activation in HepG2 cancer cells.

scholarly journals Evaluation of the Cytotoxic and Apoptogenic Effects of Glabridin and Its Effect on Cytotoxicity and Apoptosis Induced by Doxorubicin Toward Cancerous Cells

2019 ◽  
Vol 9 (3) ◽  
pp. 481-489 ◽  
Author(s):  
Masoud Modarresi ◽  
Marziyeh Hajialyani ◽  
Narges Moasefi ◽  
Farahnaz Ahmadi ◽  
Leila Hosseinzadeh
Keyword(s):  
Cancer Cells ◽  
Cytotoxic Effect ◽  
Caspase 3 ◽  
Mitochondrial Pathway ◽  
Pcr Analysis ◽  
Extrinsic Pathway ◽  
Gene Expressions ◽  
H1299 Cell ◽  
Chemotherapy Agent

Purposes: In the present study, we tried for the first time to examine the anti-proliferative and anti-apoptogenic effect of Glabridin (Glab) toward three groups of cancer cells (SKNMC, H1299, and A2780). Furthermore, the possibility of co-administration of Glab with doxorubicin (DOX) to these cells was also examined to find out whether Glab can potentiate the cytotoxic effect of this chemotherapy agent. Methods: Different cellular assays (MTT, caspase-3 activity, MMP, RT-PCR analysis) were carried out on the cancer cells treated with Glab. Results: Cellular toxicity assay revealed that Glab can potentially reduce the viability of these cells with IC50 concentrations up to 10, 12, and 38 μM toward A2780, SKNMC, and H1299 cell lines, respectively. The results of MMP and caspase-3 activity assays, in association with the results corresponding to the BAX and Bcl-2 gene expressions, altogether revealed that Glab can exert apoptogenic effect on these cells. The intrinsic mitochondrial pathway was found to be the main mechanism, in which Glab induced apoptosis toward H1299 cells and SKNMC cells, while the apoptosis mechanism for A2780 cells could be probably through extrinsic pathway. Glab also potentiated the cytotoxic effect of DOX and its accumulation in H1299 cell line. Conclusion: The results of this study revealed the promising cytotoxic role of Glab on different carcinoma cells. These data also suggested that co-chemotherapy method using Glab could be effective for treatment of cancer, but further in-vivo and clinical studies are still needed to assure these results.

Mitochondrial pathway of apoptosis and necrosis contribute to tenofovir disoproxil fumarate–induced renal damage in rats

2018 ◽  
Vol 38 (3) ◽  
pp. 288-302 ◽  
Author(s):  
H Ramamoorthy ◽  
P Abraham ◽  
B Isaac ◽  
D Selvakumar
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Renal Damage ◽  
Caspase 3 ◽  
Neutrophil Infiltration ◽  
Transcriptase Inhibitor ◽  
Mitochondrial Pathway ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Parp Activation ◽  
Apoptotic Pathway ◽  
Cyt C

Tenofovir disoproxil fumarate (TDF) is currently the only nucleotide analogue reverse-transcriptase inhibitor that is approved by the Food and Drug administration (FDA), USA, for the treatment of human immunodeficiency virus (HIV) infection. In recent days, renal toxicity is becoming common i HIV patients treated with TDF. However, the mechanism of tenofovir nephrotoxicity is not clear. We hypothesized that mitochondrial pathway of apoptosis, poly [ADP-ribose] polymerase (PARP) overactivation and neutrophil infiltration may contribute to tenofovir-induced renal damage. Renal damage was induced in adult male Wistar rats by the oral administration of 600 mg/kg body weight daily for five consecutive weeks. Kidneys were removed and used for histological and biochemical analyses. Apoptosis was detected by terminal deoxynucleotidyl transferase biotin–deoxyuridine triphosphate nick end-labelling (TUNEL) assay and caspase 3 activity and protein expression; mitochondrial pathway of apoptosis by cyt c release; and PARP activation by immunofluorescence, immunohistochemistry and Western blot techniques. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil infiltration. TDF administration resulted in increased number of TUNEL-positive cells, activation of caspase 3 and release of cyt c from mitochondria into the cytosol in the kidneys. There was increased nuclear localization of PARP as well as increase in its protein level in the TDF-treated rat kidneys. In addition, renal MPO activity was increased ninefold as compared to controls. The results of the present study show that mitochondrial apoptotic pathway, PARP overactivation and neutrophil infiltration contribute to tenofovir-induced renal damage in rats.

scholarly journals HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/12 pathway

Blood ◽  
2019 ◽  
Vol 133 (20) ◽  
pp. 2222-2232 ◽  
Author(s):  
Jung Kwon Lee ◽  
SungMyung Kang ◽  
Xidi Wang ◽  
Jesusa L. Rosales ◽  
Xu Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Ternary Complex ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Acetoxymethyl Ester ◽  
Apoptotic Pathway ◽  
Treatment Protocols

Abstract l-Asparaginase (l-ASNase) is a strategic component of treatment protocols for acute lymphoblastic leukemia (ALL). It causes asparagine deficit, resulting in protein synthesis inhibition and subsequent leukemic cell death and ALL remission. However, patients often relapse because of the development of resistance, but the underlying mechanism of ALL cell resistance to l-asparaginase remains unknown. Through unbiased genome-wide RNA interference screening, we identified huntingtin associated protein 1 (HAP1) as an ALL biomarker for l-asparaginase resistance. Knocking down HAP1 induces l-asparaginase resistance. HAP1 interacts with huntingtin and the intracellular Ca2+ channel, inositol 1,4,5-triphosphate receptor to form a ternary complex that mediates endoplasmic reticulum (ER) Ca2+ release upon stimulation with inositol 1,4,5-triphosphate3. Loss of HAP1 prevents the formation of the ternary complex and thus l-asparaginase-mediated ER Ca2+ release. HAP1 loss also inhibits external Ca2+ entry, blocking an excessive rise in [Ca2+]i, and reduces activation of the Ca2+-dependent calpain-1, Bid, and caspase-3 and caspase-12, leading to reduced number of apoptotic cells. These findings indicate that HAP1 loss prevents l-asparaginase–induced apoptosis through downregulation of the Ca2+-mediated calpain-1-Bid-caspase-3/12 apoptotic pathway. Treatment with BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester)] reverses the l-asparaginase apoptotic effect in control cells, supporting a link between l-asparaginase-induced [Ca2+]i increase and apoptotic cell death. Consistent with these findings, ALL patient leukemic cells with lower HAP1 levels showed resistance to l-asparaginase, indicating the clinical relevance of HAP1 loss in the development of l-asparaginase resistance, and pointing to HAP1 as a functional l-asparaginase resistance biomarker that may be used for the design of effective treatment of l-asparaginase-resistant ALL.

scholarly journals Antiapoptotic Proteins Bcl-2 and Bcl-XL Inhibit Clostridium difficile Toxin A-Induced Cell Death in Human Epithelial Cells

2009 ◽  
Vol 77 (12) ◽  
pp. 5400-5410 ◽  
Author(s):  
Isabelle Matte ◽  
Denis Lane ◽  
Élodie Côté ◽  
Ann-Élise Asselin ◽  
Louis-Charles Fortier ◽  
...  
Keyword(s):  
Cell Death ◽  
Clostridium Difficile ◽  
Epithelial Cells ◽  
Ovarian Carcinoma ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Colonic Cancer ◽  
Mitochondrial Pathway ◽  
Caspase 8 ◽  
Antiapoptotic Proteins

ABSTRACT It has been well established that Clostridium difficile toxin A (TcdA) induces cell death in human epithelial cells. However, the mechanism of TcdA-induced cell death remains to be fully characterized. Here, we show that TcdA induces dose-dependent cell death in ovarian carcinoma and colonic carcinoma cell lines. TcdA-mediated cell death, as well as caspase 8 and caspase 3 activation, were specifically abrogated by anti-toxin antibodies. Although caspase 8 and caspase 3 were activated by TcdA in OVCAR3 ovarian carcinoma and T84 colonic cancer cells, pancaspase and caspase 8, 3, and 9 inhibitors did not block TcdA-induced cell death. In contrast, tumor necrosis factor-related apoptosis-inducing ligand-induced cell death was nearly completely blocked by caspase inhibitors in OVCAR3 cells. In these cells, TcdA induces the mitochondrial pathway of apoptosis, as demonstrated by changes in mitochondrial outer membrane permeabilization (MOMP). Furthermore, overexpression of the antiapoptotic proteins Bcl-2 and Bcl-XL significantly inhibited TcdA-induced cell death, as well as TcdA-induced MOMP. Conversely, small interfering RNA-mediated inhibition of Bcl-XL in TcdA-resistant SKOV3ip1 cells enhanced TcdA-induced cell death. Overexpression of the antiapoptotic proteins Bcl-2 and Bcl-XL in T84 cells also inhibited TcdA-induced cell death. Altogether, our data demonstrate that TcdA induces cell death in both ovarian and colonic cancer cells preferentially via the mitochondrial pathway of apoptosis by a death receptor-independent and a caspase-independent mechanism. This process is regulated by antiapoptotic members of the Bcl-2 family.

scholarly journals Inhibition of ubiquitin-proteasome pathway activates a caspase-3-like protease and induces Bcl-2 cleavage in human M-07e leukaemic cells

1999 ◽  
Vol 340 (1) ◽  
pp. 127-133 ◽  
Author(s):  
Xue-min ZHANG ◽  
Hong LIN ◽  
Catheryne CHEN ◽  
Ben D.-M. CHEN
Keyword(s):  
Cell Death ◽  
Proteasome Inhibitor ◽  
Caspase 3 ◽  
Specific Inhibitor ◽  
Apoptotic Pathway ◽  
Principal Mechanism ◽  
Ubiquitin Proteasome Pathway ◽  
Gm Csf ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The ubiquitin-proteasome pathway is the principal mechanism for the degradation of short-lived proteins in eukaryotic cells. Here we examine the possibility that ubiquitin-proteasome is involved in regulating the levels of Bcl-2, which is abundantly expressed in M-07e cells, a granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent human leukaemic cell line. Apoptosis in M-07e cells, induced by GM-CSF withdrawal, was associated with a gradual cleavage of Bcl-2 into a 22 kDa fragment. Treatment of M-07e cells with benzyloxycarbonyl-Leu-Leu-L-leucinal (Z-LLL-CHO; MG-132), a reversible ubiquitin-proteasome inhibitor, markedly accelerated the cleavage of Bcl-2 and promoted cell death through the apoptotic pathway. The cleavage of Bcl-2 was inhibited by a caspase-3 (CPP32)-specific inhibitor [acetyl-Asp-Glu-Val-Asp-CHO (DEVD-CHO)] but not caspase 1 inhibitor (acetyl-Tyr-Val-Ala-Asp-CHO), suggesting that Bcl-2 is a proteolytic substrate of a caspase-3-like protease activated during apoptosis. The simultaneous addition of recombinant human GM-CSF (rhGM-CSF) to M-07e cultures delayed the activation of caspase 3 and Bcl-2 cleavage triggered by Z-LLL-CHO, suggesting that the activation of the GM-CSF signalling pathway can partly overcome the apoptotic effect induced by Z-LLL-CHO. Apoptosis induced by inhibition of the proteasome pathway was verified in studies with lactacystin, a highly specific and irreversible proteasome inhibitor. Lactacystin-induced apoptosis in M-07e cells was remarkably similar to that induced by Z-LLL-CHO, which included caspase 3 activation, cleavage of Bcl-2 into a 22 kDa fragment and, ultimately, cell death. These results showed that inhibition of the ubiquitin-proteasome pathways can lead to the activation of a DEVD-CHO-sensitive caspase and induces Bcl-2 cleavage, which might have a role in mediating apoptosis in M-07e cells.

scholarly journals Human Parvovirus B19 Nonstructural (NS1) Protein Induces Apoptosis in Erythroid Lineage Cells

1998 ◽  
Vol 72 (4) ◽  
pp. 3018-3028 ◽  
Author(s):  
Stanley Moffatt ◽  
Nobuo Yaegashi ◽  
Kohtaro Tada ◽  
Nobuyuki Tanaka ◽  
Kazuo Sugamura
Keyword(s):  
Cell Death ◽  
Cell Line ◽  
Transcriptional Activation ◽  
Caspase 3 ◽  
Parvovirus B19 ◽  
Regulatory System ◽  
Nucleoside Triphosphate ◽  
Human Parvovirus B19 ◽  
Ns1 Protein ◽  
Apoptotic Pathway

ABSTRACT Infection of erythroid-lineage cells by human parvovirus B19 is characterized by a gradual cytocidal effect. Accumulating evidence now implicates the nonstructural (NS1) protein of the virus in cytotoxicity, but the mechanism underlying the NS1-induced cell death is not known. Using a stringent regulatory system, we demonstrate that NS1 cytotoxicity is closely related to apoptosis, as evidenced by cell morphology, genomic DNA fragmentation, and cell cycle analysis with the human erythroleukemia cell line K562 and the erythropoietin-dependent megakaryocytic cell line UT-7/Epo. Apoptosis was significantly inhibited by an interleukin-1β (IL-1β)-converting enzyme (ICE)/CED-3 family protease inhibitor, Ac-DEVD-CHO (CPP32; caspase 3), whereas a similar inhibitor of ICE (caspase 1), Ac-YVAD-CHO, had no effect. Furthermore, stable expression of the human Bcl-2 proto-oncogene resulted in near-total protection from cell death in response to NS1 induction. Mutations engineered into the nucleoside triphosphate-binding domain of NS1 significantly rescued cells from NS1-induced apoptosis without having any effect on NS1-induced activation of the IL-6 gene expression which is mediated by NF-κB. Furthermore, using pentoxifylline, an inhibitor of NF-κB activation, we demonstrate that the NF-κB-mediated IL-6 activation by NS1 is uncoupled from the apoptotic pathway. This functional dissection indicates a complexity underlying the biochemical function of human parvovirus NS1 in transcriptional activation and induction of apoptosis. Our findings indicate that NS1 of parvovirus B19 induces cell death by apoptosis in at least erythroid-lineage cells by a pathway that involves caspase 3, whose activation may be a key event during NS1-induced cell death.

scholarly journals Triclabendazole Induces Pyroptosis by Activating Caspase-3 to Cleave GSDME in Breast Cancer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Liang Yan ◽  
Yi Liu ◽  
Xue-feng Ma ◽  
Dan Hou ◽  
Yu-hui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Xenograft Model ◽  
Specific Inhibitor ◽  
Apoptotic Pathway ◽  
Mitochondrial Apoptotic Pathway ◽  
Protein Levels

Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME–N-terminal fragment cleavage and pyroptosis were reduced by caspase-3–specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.

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