O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells

The combination of chemotherapy with chemosensitizing agents is a common approach to enhance anticancer activity while reducing the dose-dependent adverse side effects of cancer treatment. Herein, we investigated doxorubicin (DOX) and O-GlcNAc transferase (OGT) inhibitor OSMI-1 combination treatment, which significantly enhanced apoptosis in hepatocellular carcinoma cells (HepG2) as a result of synergistic drug action in disparate stress signaling pathways. Treatment with a low dose of DOX or a suboptimal dose of OSMI-1 alone did not induce apoptotic cell death in HepG2 cells. However, the combination of DOX with OSMI-1 in HepG2 cells synergistically increased apoptotic cell death through the activation of both the p53 and mitochondrial Bcl2 pathways compared to DOX alone. We also demonstrated that the combination of DOX and OSMI-1 stimulated cell death, dramatically reducing cell proliferation and tumor growth in vivo using a HepG2 xenograft mouse model. These findings indicate that OSMI-1 acts as a potential chemosensitizer by enhancing DOX-induced cell death. This study provides insight into a possible mechanism of chemotherapy resistance, identifies potential novel drug targets, and suggests that OGT inhibition could be utilized in clinical applications to treat hepatocellular carcinoma as well as other cancer types.

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Inhibition of cytochrome P450 2J2 by tanshinone IIA induces apoptotic cell death in hepatocellular carcinoma HepG2 cells

European Journal of Pharmacology ◽

10.1016/j.ejphar.2015.07.047 ◽

2015 ◽

Vol 764 ◽

pp. 480-488 ◽

Cited By ~ 25

Author(s):

Yu Jin Jeon ◽

Joong Sun Kim ◽

Geun Hye Hwang ◽

Zhexue Wu ◽

Ho Jae Han ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Cytochrome P450 ◽

Hepg2 Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Tanshinone Iia

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Non-apoptotic cell death induced by opening the large conductance mechanosensitive channel MscL in hepatocellular carcinoma HepG2 cells

Biomaterials ◽

10.1016/j.biomaterials.2020.120061 ◽

2020 ◽

Vol 250 ◽

pp. 120061

Author(s):

Xiaoxu Wen ◽

Siyang Tang ◽

Feifan Hong ◽

Xiaomin Wang ◽

Sihan Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Hepg2 Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Mechanosensitive Channel

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Contribution of TNF-α to Leukocyte Adhesion, Vascular Leakage, and Apoptotic Cell Death in Endotoxin-Induced Uveitis In Vivo

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.02-0589 ◽

2003 ◽

Vol 44 (5) ◽

pp. 2184 ◽

Cited By ~ 91

Author(s):

Kan Koizumi ◽

Vassiliki Poulaki ◽

Sven Doehmen ◽

Gerhard Welsandt ◽

Sven Radetzky ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Leukocyte Adhesion ◽

Apoptotic Cell Death ◽

Vascular Leakage ◽

Tnf Α

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Isoflavones Isolated from the Seeds of Millettia ferruginea Induced Apoptotic Cell Death in Human Ovarian Cancer Cells

Molecules ◽

10.3390/molecules25010207 ◽

2020 ◽

Vol 25 (1) ◽

pp. 207 ◽

Cited By ~ 2

Author(s):

Yi-Yue Wang ◽

Jun Hyeok Kwak ◽

Kyung-Tae Lee ◽

Tsegaye Deyou ◽

Young Pyo Jang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Death ◽

Cancer Cells ◽

Caspase 3 ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Millettia Ferruginea ◽

Induced Apoptosis

The seeds of Millettia ferruginea are used in fishing, pesticides, and folk medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from M. ferruginea were evaluated in human ovarian cancer cells. We found that isoflavone ferrugone and 6,7-dimethoxy-3’,4’-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone and DMI treatment increased the sub-G1 cell population in a dose-dependent manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was associated with the induction of apoptosis, as shown by an increase in annexin V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk, a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced apoptosis, suggesting that cell death stimulated by the isoflavones is mediated by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was found to be caspase-8-dependent, while DMI-induced apoptosis was caspase-9-dependent. Notably, DMI, but not ferrugone, increased the intracellular levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These data suggest that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells.

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Neuroprotective Effects of Alpha-Mangostin on MPP+-Induced Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells

Journal of Toxicology ◽

10.1155/2015/919058 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 21

Author(s):

Prachya Janhom ◽

Permphan Dharmasaroja

Keyword(s):

Cell Death ◽

Cell Viability ◽

Caspase 3 ◽

Nuclear Dna ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Concomitant Treatment ◽

Ros Production ◽

Cellular Models ◽

Induced Apoptosis

In vitrostudies have shown that extracts from mangosteen (Garcinia mangostanaLinn.) act as antioxidants and cytoprotective agents against oxidative damage. The protective effect of alpha-mangostin, the major xanthone found in the pericarp of the mangosteen, in cellular models of Parkinson’s disease (PD), has not been investigated. This study aims to investigate whether alpha-mangostin could protect SH-SY5Y neuroblastoma cells from MPP+-induced apoptosis. The effects of alpha-mangostin on MPP+-induced cell death were evaluated with a cell viability assay, staining for nuclear DNA morphology, flow cytometry for apoptotic cells and reactive oxygen species (ROS) production, quantitative real-time PCR for the expression of p53, Bax, and Bcl-2, and western blot analysis for cleaved caspase-3. Concomitant treatment with alpha-mangostin attenuated the effect of MPP+on cell viability and apoptotic cell death. Alpha-mangostin reduced ROS formation induced by MPP+. Bax/Bcl-2 expression ratio and expression of p53 were significantly lower in cells cocultured with alpha-mangostin and MPP+. The cotreated cells showed a significant decrease in activated caspase-3 compared with MPP+treatment alone. Our data suggest that cytoprotection of alpha-mangostin against MPP+-induced apoptosis may be associated with the reduction of ROS production, modulating the balance of pro- and antiapoptotic genes, and suppression of caspase-3 activation.

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Abstract 1045: Enhancement of drug-induced apoptotic cell death in human hepatocellular carcinoma cells with knock-down of BNIP3

10.1158/1538-7445.am10-1045 ◽

2010 ◽

Author(s):

Pak Lun Yau ◽

Tsun Yee Tsang ◽

Ngai Na Co ◽

Siu Cheong Choi ◽

Chi Lam Au Yeung ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Drug Induced ◽

Hepatocellular Carcinoma Cells ◽

Knock Down ◽

Human Hepatocellular Carcinoma Cells

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Ginkgo biloba Prevents Oxidative Stress-Induced Apoptosis Blocking p53 Activation in Neuroblastoma Cells

Antioxidants ◽

10.3390/antiox9040279 ◽

2020 ◽

Vol 9 (4) ◽

pp. 279 ◽

Cited By ~ 2

Author(s):

Francesco Di Meo ◽

Rossana Cuciniello ◽

Sabrina Margarucci ◽

Paolo Bergamo ◽

Orsolina Petillo ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neurodegenerative Diseases ◽

Ginkgo Biloba ◽

Apoptotic Cell ◽

Neuroblastoma Cells ◽

Apoptotic Cell Death ◽

Parp Cleavage ◽

Egb 761 ◽

Induced Apoptosis

Oxidative stress has been associated to neuronal cell loss in neurodegenerative diseases. Neurons are post-mitotic cells that are very sensitive to oxidative stress—especially considering their limited capacity to be replaced. Therefore, reduction of oxidative stress, and inhibiting apoptosis, will potentially prevent neurodegeneration. In this study, we investigated the neuroprotective effect of Ginkgo biloba extract (EGb 761) against H2O2 induced apoptosis in SK-N-BE neuroblastoma cells. We analysed the molecular signalling pathway involved in the apoptotic cell death. H2O2 induced an increased acetylation of p53 lysine 382, a reduction in mitochondrial membrane potential, an increased BAX/Bcl-2 ratio and consequently increased Poly (ADP-ribose) polymerase (PARP) cleavage. All these effects were blocked by EGb 761 treatment. Thus, EGb 761, acting as intracellular antioxidant, protects neuroblastoma cells against activation of p53 mediated pathway and intrinsic mitochondrial apoptosis. Our results suggest that EGb 761, protecting against oxidative-stress induced apoptotic cell death, could potentially be used as nutraceutical for the prevention and treatment of neurodegenerative diseases.

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Redistribution of phosphatidylethanolamine and phosphatidylserine precedes reperfusion-induced apoptosis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.1.h242 ◽

1998 ◽

Vol 274 (1) ◽

pp. H242-H248 ◽

Cited By ~ 11

Author(s):

Nilanjana Maulik ◽

Valerian E. Kagan ◽

Vladimir A. Tyurin ◽

Dipak K. Das

Keyword(s):

Cell Death ◽

Dna Fragmentation ◽

Genomic Dna ◽

High Performance ◽

Apoptotic Cell ◽

Ischemia Reperfusion ◽

Apoptotic Cell Death ◽

Dna Laddering ◽

Outer Leaflet ◽

Induced Apoptosis

Although cardiomyocyte death and infarction associated with ischemia-reperfusion are traditionally believed to be induced via necrosis, recent studies implicated apoptotic cell death in ischemic reperfused tissue. To examine whether myocardial ischemic reperfusion injury is mediated by apoptotic cell death, isolated perfused rat hearts were subjected to 15 and 30 min of ischemia as well as 15 min of ischemia followed by 30, 90, or 120 min of reperfusion. At the end of each experiment, hearts were processed for the evaluation of apoptosis and DNA laddering. Apoptosis was studied by visualizing the apoptotic cardiomyocytes by direct fluorescence detection of digoxigenin-labeled genomic DNA using APOPTAG in situ apoptosis detection kit. DNA laddering was evaluated by subjecting the DNA obtained from cardiomyocytes to 1.8% agarose gel electrophoresis and photographed under ultraviolet illumination. In addition, high-performance thin-layer chromatography (HPTLC) of aminophospholipids labeled with 2,4,6-trinitrobenzenesulfonate was performed to evaluate phospholipid topography in cardiomyocytes. The results of our study revealed apoptotic cells only in the 90- and 120-min reperfused hearts as demonstrated by the intense fluorescence of the immunostained digoxigenin-labeled genomic DNA when observed under fluorescence microscope. None of the ischemic hearts showed any evidence of apoptosis. These results corroborated with the findings of DNA fragmentation that showed increased ladders of DNA bands in the 120-min reperfused hearts, representing integer multiples of the internucleosomal DNA length (∼180 bp). Two-dimensional HPTLC of the phospholipids obtained from the cardiomyocytes and transbilayer organization of the phosphatidylethanolamine (PE) and phosphatidylserine (PS) in the myocytes indicated translocation of both PE and PS from the inner leaflet to the outer leaflet of the membrane as early as after 20 min of ischemia. These results demonstrate that the redistribution of PS and PE precedes the apototic cell death and DNA fragmentation associated with the reperfusion of ischemic myocardium, suggesting that ischemia may trigger the signal for apoptosis although it becomes evident during reperfusion.

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