scholarly journals A Diamine-PEGylated Oleanolic Acid Derivative Induced Efficient Apoptosis through a Death Receptor and Mitochondrial Apoptotic Pathway in HepG2 Human Hepatoma Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1375
Author(s):  
Fatin Jannus ◽  
Marta Medina-O’Donnell ◽  
Francisco Rivas ◽  
Luis Díaz-Ruiz ◽  
Eva E. Rufino-Palomares ◽  
...  
Keyword(s):  
Oleanolic Acid ◽  
Death Receptor ◽  
Cancer Therapies ◽  
Caspase 9 ◽  
Human Hepatoma Cells ◽  
Apoptotic Pathway ◽  
Cycle Arrest ◽  
Growth Inhibitory ◽  
Apoptotic Pathways ◽  
Oleanolic Acid Derivative

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell line. The cytotoxicity results showed that HepG2 cell viability was markedly reduced, with a very low 50% of cell growth inhibitory concentration (IC50, 0.14 µg/mL). We then investigated the anti-tumor mechanisms of OADP in HepG2 cells. The flow-cytometry analysis was used to evaluate cell apoptosis, indicating that 74–95% of cells were apoptotic. OADP caused cell cycle arrest in the G0/G1 phase and the loss of the mitochondrial membrane potential (MMP). Western blot analysis was performed to assess the expression levels of key proteins associated with the underlying molecular mechanism. The results showed the clear upregulation of caspase-8, caspase-9, caspase-3, Bak, p21, and p53, accompanied by the downregulation of Bcl-2. Similar results were obtained by the cotreatment with OADP and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Agents such as OADP, which are capable of activating extrinsic and intrinsic apoptotic pathways, may represent potential HCC cancer therapies.

scholarly journals L-securinine inhibits cell growth and metastasis of human androgen-independent prostate cancer DU145 cells via regulating mitochondrial and AGTR1/MEK/ERK/STAT3/PAX2 apoptotic pathways

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Dongxu Zhang ◽  
Houxian Liu ◽  
Binbin Yang ◽  
Jiasheng Hu ◽  
Yue Cheng
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Annexin V ◽  
Inhibitory Effect ◽  
Apoptotic Pathway ◽  
Growth Inhibitory ◽  
Du145 Cells ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Androgen Independent

Abstract The present study aims to evaluate the anticancer effect of L-securinine on androgen-independent prostate cancer (AIPC) DU145 cells. L-securinine (2.5, 5, and 10 μM) treatment for 24, 48 and 72 h displayed strong growth inhibitory effect on DU145 cells in a concentration and time-dependent fashion but has less toxicity toward normal androgen-dependent LNCaP cells. Hoechst 332582 staining of DU145 cells and Annexin V-FITC/ PI dual-labeling followed by flow cytometry assay identified that this growth inhibition by L-securinine would be due to the induction of apoptosis. Moreover Transwell assay revealed that L-securinine significantly inhibited the cell migration/invasion ability of DU145 cells. Furthermore, results of western blotting showed that the involvement of mitochondrial apoptotic pathway in the L-securinine-induced apoptosis of DU145 cell, as evidenced by an increase in the protein expression of Bax, cleaved caspase-9, cleaved caspase-3, cytosolic cytochrome c, and cleaved PARP, together with a unchanged cleaved caspase-8 and decreased Bcl-2 protein expression. Also, L-securinine-induced antimetastatic activity in DU145 cells was associated with decreased protein expression of MMP-2 and MMP-9 and concurrent reduction of VEGF. In addition, further studies revealed that L-securinine may inhibit the protein expression of AGTR1, p-MEK1/2, p-ERK1/2, p-STAT3, PAX2, and p-PAX2, while the expression of ERK1/2, MEK1/2, and STAT3 protein retains intact. These findings suggest that L-securinine may be a promising chemopreventive agent against AIPC.

Apaf-1 and caspase-9 are required for cytokine withdrawal-induced apoptosis of mast cells but dispensable for their functional and clonogenic death

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 1872-1877 ◽  
Author(s):  
Vanessa S. Marsden ◽  
Thomas Kaufmann ◽  
Lorraine A. O'Reilly ◽  
Jerry M. Adams ◽  
Andreas Strasser
Keyword(s):  
Mast Cells ◽  
Fetal Liver ◽  
Wild Type ◽  
Caspase 9 ◽  
Receptor Stimulation ◽  
Apoptotic Pathway ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Cytokine Deprivation

Cytokines promote survival of mast cells by inhibiting apoptotic pathways regulated by the Bcl-2 protein family. We previously showed that lymphocyte apoptosis can proceed via a Bcl-2-inhibitable pathway independent of the canonical initiator caspase, caspase-9, and its adaptor, Apaf-1. Here we report that mast cells lacking caspase-9 or Apaf-1 are refractory to apoptosis after cytotoxic insults but still lose effector function and ability to proliferate. In response to cytokine deprivation or DNA damage, fetal liver-derived mast cells lacking Apaf-1 or caspase-9 failed to undergo apoptosis. Nevertheless, the cytokine-starved cells were not functionally alive, because, unlike those overexpressing Bcl-2, they could not degranulate on Fcϵ receptor stimulation or resume proliferation on re-addition of cytokine. Furthermore, mast cells lacking Apaf-1 or caspase-9 had no survival advantage over wild-type counterparts in vivo. These results indicate that the Apaf-1/caspase-9-independent apoptotic pathway observed in lymphocytes is ineffective in cytokine-deprived mast cells. However, although Apaf-1 and caspase-9 are essential for mast cell apoptosis, neither is required for the functional or clonogenic death of the cells, which may be due to mitochondrial dysfunction.

scholarly journals The oleanolic acid derivative, 3-O-succinyl-28-O-benzyl oleanolate, induces apoptosis in B16–F10 melanoma cells via the mitochondrial apoptotic pathway

RSC Advances ◽  
2016 ◽  
Vol 6 (96) ◽  
pp. 93590-93601 ◽  
Author(s):  
Fernando J. Reyes-Zurita ◽  
Marta Medina-O'Donnell ◽  
Rosa M. Ferrer-Martin ◽  
Eva E. Rufino-Palomares ◽  
Samuel Martin-Fonseca ◽  
...  
Keyword(s):  
Acid Derivative ◽  
Oleanolic Acid ◽  
Melanoma Cells ◽  
Skin Melanoma ◽  
Apoptotic Pathway ◽  
Mitochondrial Apoptotic Pathway ◽  
Oleanolic Acid Derivative

Antiproliferative and proapoptotic effects of 3-O-succinyl-28-O-benzyl oleanolate on B16–F10 skin-melanoma cells.

scholarly journals Prep1 Directly Regulates the Intrinsic Apoptotic Pathway by Controlling Bcl-XL Levels

2008 ◽  
Vol 29 (5) ◽  
pp. 1143-1151 ◽  
Author(s):  
Nicola Micali ◽  
Carmelo Ferrai ◽  
Luis C. Fernandez-Diaz ◽  
Francesco Blasi ◽  
Massimo P. Crippa
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Annexin V ◽  
Genotoxic Stress ◽  
Binding Activity ◽  
Caspase 9 ◽  
Apoptotic Pathway ◽  
Mitochondrial Homeostasis ◽  
P53 Response ◽  
Novel Target ◽  
Apoptotic Pathways

ABSTRACT The Prep1 homeodomain transcription factor is essential in embryonic development. Prep1 hypomorphic mutant mouse (Prep1 i/i ) embryos (embryonic day 9.5) display an increased terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling reaction compared to wild-type (WT) littermates. Prep1 i/i mouse embryo fibroblasts (MEFs) show an increased basal level of annexin V binding activity, reduction of the mitochondrial-membrane potential, and increased caspase 9 and 3 activation, indicating increased apoptosis. Prep1 i/i MEFs also respond faster than WT MEFs to genotoxic stress, indicating increased activation of the intrinsic apoptotic pathways. We did not observe an increase in p53 or an abnormal p53 response to apoptotic stimuli. However, hypomorphic MEFs have decreased endogenous levels of antiapoptotic Bcl-XL mRNA and protein, and Bcl-x overexpression rescues the defect of Prep1 i/i MEFs. Using transient transfections and chromatin immunoprecipitation, we identified the Bcl-x promoter as a novel target of Prep1. Thus, Prep1 directly controls mitochondrial homeostasis (and the apoptotic potential) by modulating Bcl-x gene expression.

The coexistence of nocturnal sustained hypoxia and obesity additively increases cardiac apoptosis

2008 ◽  
Vol 104 (4) ◽  
pp. 1144-1153 ◽  
Author(s):  
Shin-Da Lee ◽  
Wei-Wen Kuo ◽  
Da-Tian Bau ◽  
Fu-Yang Ko ◽  
Fong-Li Wu ◽  
...  
Keyword(s):  
Death Receptor ◽  
Left Ventricular ◽  
Heart Weight ◽  
Apoptotic Pathway ◽  
Apoptotic Protein ◽  
Blood Pressures ◽  
Old Rats ◽  
Apoptotic Pathways ◽  
Whole Heart ◽  
Sustained Hypoxia

Background: nocturnal sustained hypoxia during sleeping time has been reported in severe obesity, but no information regarding the cardiac molecular mechanism in the coexistence of nocturnal sustained hypoxia and obesity is available. This study evaluates whether the coexistence of nocturnal sustained hypoxia and obesity will increase cardiac Fas death receptor and mitochondrial-dependent apoptotic pathway. Methods: 32 lean and 32 obese 5- to 6-mo-old rats with or without nocturnal sustained hypoxia were studied and assigned to one of four subgroups: normoxia lean (NL), normoxia obese (NO), hypoxia lean (HL, 12% O2 for 8 h and 21% O2 16 h/day, 1 wk), and hypoxia obese (HO). The heart weight index, tail cuff plethysmography, echocardiography, hematoxylin-eosin staining, TUNEL assays, Western blotting, and RT-PCR were performed. Results: systolic and diastolic blood pressures in HO were higher than those in NL, and fractional shortening in HO was reduced compared with others. The whole heart weight, the left ventricular weight, the abnormal myocardial architecture, and TUNEL-positive apoptotic cells, as well as the activity of cardiac Fas-dependent and mitochondrial-dependent apoptotic pathway, were significantly increased in obese group or nocturnal sustained hypoxia group and were further increased when obesity and nocturnal sustained hypoxia coexisted, the evidence for which is based on decreases in an anti-apoptotic protein Bcl2 level and Bid and increases in Fas, FADD, pro-apoptotic Bad, BNIP3, cytosolic cytochrome c, activated caspase-8, activated caspase-9, and activated caspase-3. Conclusions: The cardiac Fas receptor- and mitochondrial-dependent apoptotic pathways were more activated in obesity with coexistent nocturnal sustained hypoxia, which may represent one possible apoptotic mechanism for the development of heart failure in obesity with nocturnal sustained hypoxia.

scholarly journals Therapeutics Targeting the Core Apoptotic Machinery

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2618
Author(s):  
Claudia Hamilton ◽  
Jennifer P. Fox ◽  
Daniel B. Longley ◽  
Catherine A. Higgins
Keyword(s):  
Cancer Cells ◽  
Death Receptor ◽  
Cancer Therapeutics ◽  
Clinical Development ◽  
Apoptotic Pathway ◽  
Resistance Factors ◽  
Anti Cancer ◽  
Apoptosis Pathways ◽  
Direct Targeting ◽  
Apoptotic Pathways

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.

scholarly journals IFN-?induces cell death in human hepatoma cells through a trail/death receptor-mediated apoptotic pathway

2001 ◽  
Vol 93 (2) ◽  
pp. 262-268 ◽  
Author(s):  
Eui-Cheol Shin ◽  
Ju Mi Ahn ◽  
Chul Hoon Kim ◽  
Youjeong Choi ◽  
Young Soo Ahn ◽  
...  
Keyword(s):  
Cell Death ◽  
Death Receptor ◽  
Hepatoma Cells ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Apoptotic Pathway ◽  
Trail Death Receptor

scholarly journals Antiapoptotic and mitochondrial biogenetic effects of exercise training on ovariectomized hypertensive rat hearts

2019 ◽  
Vol 126 (6) ◽  
pp. 1661-1672 ◽  
Author(s):  
Yi-Yuan Lin ◽  
Yi Hong ◽  
Shao-Hong Yu ◽  
Xu-Bo Wu ◽  
Woei-Cherng Shyu ◽  
...  
Keyword(s):  
Exercise Training ◽  
Mitochondrial Biogenesis ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Death Domain ◽  
Caspase 9 ◽  
Apoptotic Pathway ◽  
Fas Receptor ◽  
Protein Levels ◽  
Apoptotic Pathways

This study was to investigate the effects of exercise training on antiapoptotic pathways and mitochondrial biogenesis in ovariectomized hypertensive rats. Histopathological analysis, TUNEL assay, and Western blotting were performed on the excised hearts from female spontaneously hypertensive rats (SHR), which were divided into a sham-operated sedentary hypertensive (SHR-S), a sedentary hypertensive ovariectomized (SHR-O), and hypertensive ovariectomized rats that underwent treadmill exercise training (SHR-OT; 60 min/day, 5 days/wk) for 8 wk, along with normotensive Wistar Kyoto rats (WKY). When compared with the WKY group, the SHR-S group exhibited decreased protein levels of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial OPA-1 (mitochondrial biogenesis) and decreased further in the SHR-O group. The protein levels of p-PI3K, p-Akt, Bcl-2, Bcl-xL (prosurvival pathways), and the protein levels of PGC-1α and mitochondrial OPA1 (mitochondrial biogenesis) were increased in the SHR-OT group, but estrogen receptor (ER)α and ERβ were not changed when compared with the SHR-O group. The protein levels of t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3 (mitochondria-dependent apoptotic pathways), as well as Fas ligand, TNF-α, Fas receptors, Fas-associated death domain, activated caspase 8 (Fas receptor-dependent apoptotic pathways) were decreased in the SHR-OT group, when compared with the SHR-O group. Exercise training protection on the coexistence of hypertension and ovariectomy-induced cardiac mitochondria-dependent and Fas receptor-dependent apoptotic pathways by enhancing the Bcl2-related and mitochondrial biogenetic prosurvival pathways might provide a new therapeutic effect on cardiac protection in oophorectomized early postmenopausal hypertensive women. NEW & NOTEWORTHY Widely dispersed cardiac apoptosis was found in the coexistence of hypertension and ovariectomy. Exercise training on a treadmill could prevent ovariectomized hypertension-induced widely dispersed cardiac apoptosis via mitochondria-dependent apoptotic pathway (t-Bid, Bad, Bax, cytosolic cytochrome c, activated caspase 9, and activated caspase 3) and Fas receptor-dependent apoptotic pathway (Fas ligand, tumor necrosis factor-α, Fas receptors, Fas-associated death domain, activated caspase 8, and activated caspase 3) through enhancing the Bcl2-related (p-PI3K, p-Akt, Bcl-2, Bcl-xL) and mitochondrial biogenetic (PGC-1α and mitochondrial optic atrophy 1) prosurvival pathways.

scholarly journals The Apoptosis Induction of Oleandrin on Osteosarcoma Cells through Regulating Mitochondrial- and Death Receptor-Dependent Apoptotic Pathways in Vitro

2016 ◽  
Author(s):  
Yunlong Ma ◽  
Bin Zhu ◽  
Lei Yong ◽  
Chunyu Song ◽  
Xiao Liu ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Treatment Time ◽  
Death Receptor ◽  
Caspase 8 ◽  
Osteosarcoma Cells ◽  
Caspase 9 ◽  
Apoptotic Pathway

Our previous study has found the anti-tumor activity of oleandrin in osteosarcoma cells in vitro, but the signal transduction process of cell apoptosis induced by oleandrin is uncertain, which is explored in this study. Fluorescence staining and flow cytometry (FCM) was performed to detect the cell apoptosis, intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Caspase-3 activity was detected using a commercial kit. The protein expression of cytoplasmic cytochrome c, mitochondrial cytochrome c, bcl-2, bax, caspase-9, Fas, FasL, caspase-8 and caspase-3 was detected using western blot. A pan-caspase inhibitor, z-VAD-fmk, was applied to block the apoptotic pathway and the apoptosis status were re-tested. We found that oleandrin significantly induced the increased apoptosis of U2OS cells. Meanwhile, the intracellular ROS was elevated, but the MMP decreased. The cytochrome c in mitochondria was notably decreased but increased in cytoplasm. The caspase-3 activity was also enhanced with the increase of drug concentration and treatment time. Oleandrin also down-regulated the level of bcl-2, but remarkably up-regulated the expression of bax, cleaved caspase-9, Fas, FasL, cleaved caspase-8 and cleaved caspase-3. Furthermore, the pre-treatment with z-VAD-fmk almost completely reverted the oleandrin-induced apoptosis. The results suggested that oleandrin induces the apoptosis of osteosarcoma cells via mitochondrial- and death receptor-dependent pathways.

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