scholarly journals The Pyridone-Annelated Isoindigo (5‘-Cl) Induces Apoptosis, Dysregulation of Mitochondria and Formation of ROS in Leukemic HL-60 Cells

2015 ◽  
Vol 35 (5) ◽  
pp. 1958-1974 ◽  
Author(s):  
Ayman M. Saleh ◽  
Ahmad Aljada ◽  
Mustafa M. El-Abadelah ◽  
Salim S. Sabri ◽  
Jalal A. Zahra ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Staining ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Mitochondrial Functions ◽  
Apoptotic Activity ◽  
Induced Apoptosis

Background/Aims: In our quest to develop an isoindigo with improved efficacy and bioavailability, we recently synthesized a series of novel substituted pyridone-annelated isoindigo and evaluated their antiproliferative effects. We identified the compound [(E)-1-(5'-Chloro-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f] quinoline-8-carboxylic acid], abbreviated as 5'-Cl, which shows selective antiproliferative activities against various cancer cell lines mediated through apoptosis. Here we have investigated the molecular mechanisms underlying the apoptotic activity of 5'-Cl in the human promyelocytic leukemia HL-60 cells. Methods: We employed different methods to determine the apoptotic pathways triggered by 5'-Cl in HL-60 cells, using flow cytometry, nuclear staining, caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and Western blotting techniques. Results: Low concentrations (1-8 µM) of 5'-Cl inhibited the growth of HL-60 cells in a dose and time-dependent manner. Cytotoxicity of this compound is found to be mediated by a caspase-dependent apoptosis. Also, there were indications of caspase independent apoptosis as z-VAD-FMK failed to fully rescue the cells from 5‘-Cl-induced apoptosis. In addition, the compound triggered generation of Reactive Oxygen Species (ROS), caused depolarization of the mitochondrial inner membrane, decreased the level of cellular ATP, modulated the expression and phosphorylation of Bcl-2 leading to loss of its association with Bax and increased the release of cytochrome c to the cytosol of treated cells. The effects of 5‘-Cl on mitochondria and apoptosis were substantially blocked in the presence of a combination between z-VAD-FMK and either of the ROS scavenger N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC). Conclusion: We demonstrated that the growth inhibitory effects of 5'-Cl in HL-60 cells involve multiple pathways of apoptosis and dysregulation of mitochondrial functions.

The molecular mechanisms of Phytophthora infestans in response to reactive oxygen species (ROS) stress

2021 ◽  
Author(s):  
Xiumei Luo ◽  
Tingting Tian ◽  
Maxime Bonnave ◽  
Xue Tan ◽  
Xiaoqing Huang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Late Blight ◽  
Phytophthora Infestans ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Microbial Pathogens ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Tor Signaling ◽  
Potato Resistance

Reactive oxygen species (ROS) are critical for the growth, development, proliferation, and pathogenicity of microbial pathogens; however, excessive levels of ROS are toxic. Little is known regarding the signaling cascades in response to ROS stress in oomycetes such as Phytophthora infestans, the causal agent of potato late blight. Here, P. infestans was used as a model system to investigate the mechanism underlying the response to ROS stress in oomycete pathogens. Results showed severe defects in sporangium germination, mycelial growth, appressorium formation, and virulence of P. infestans in response to H2O2 stress. Importantly, these phenotypes mimic those of P. infestans treated with rapamycin, the inhibitor of target of rapamycin (TOR, 1-phosphatidylinositol-3-kinase). Strong synergism occurred when P. infestans was treated with a combination of H2O2 and rapamycin, suggesting that a crosstalk exists between ROS stress and the TOR signaling pathway. Comprehensive analysis of transcriptome, proteome and phosphorylation omics showed that H2O2 stress significantly induced the operation of the TOR-mediated autophagy pathway. Monodansylcadaverine (MDC) staining showed that in the presence of H2O2 and rapamycin, the autophagosome level increased in a dosage-dependent manner. Furthermore, transgenic potatoes containing double-stranded RNA of PiTOR (TOR in P. infestans) displayed high resistance to P. infestans. Taken together, TOR is involved in the ROS response and is a potential target for control of oomycete diseases, as host-mediated silencing of PiTOR enhances potato resistance to late blight.

The Requirement of Reactive Oxygen Species Generation in the Apoptosis of Leukemia Cells Induced by 2-Methoxyestradiol.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4370-4370
Author(s):  
Guo Kunyuan ◽  
Miaorong She ◽  
Haiyan Hu ◽  
Xinqing Niu ◽  
Sanfang Tu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Leukemia Cell ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Ros Generation ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Induced Apoptosis

Abstract 2-Methoxyestradiol (2-ME) is a new anticancer agent currently under investigation for treatment of leukemia. We evaluated the effects of 2-ME-induced apoptosis in two myeloid leukemia cell lines (U937 and HL-60) in association with reactive oxygen species (ROS) generation. We found that 2-ME resulted in viability decrease in a dose-dependent manner, generated ROS: nitric oxide and superoxide anions, and mitochondria damage. 2-ME-induced apoptosis correlated with increase in ROS. Quenching of ROS with N-acetyl-L-cysteine protected leukemia cells from the cytotoxicity of 2-ME and prevented apoptosis induction by 2-ME. Furthermore, addition of manumycin, a farnesyltransferase inhibitor, demonstrated by our previous studies that induced apoptosis of leukemic cells and induced ROS, significantly enhanced the apoptosis-induced by 2-ME. In conclusion, cellular ROS generation play an important role in the cytotoxic effect of 2-ME. It is possible to use ROS-generation agents such as manumycin to enhance the antileukemic effect. Such a combination strategy need the further in vivo justify and may have potential clinical application.

scholarly journals Bufalin Induces Reactive Oxygen Species Dependent Bax Translocation and Apoptosis in ASTC-a-1 Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Lei Sun ◽  
Tongsheng Chen ◽  
Xiaoping Wang ◽  
Yun Chen ◽  
Xunbin Wei
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Temporal Dynamics ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Induced Apoptosis

Bufalin has been shown to induce cancer cell death through apoptotic pathways. However, the molecular mechanisms are not well understood. In this study, we used the confocal fluorescence microscopy (CFM) to monitor the spatio-temporal dynamics of reactive oxygen species (ROS) production, Bax translocation and caspase-3 activation during bufalin-induced apoptosis in living human lung adenocarcinoma (ASTC-a-1) cells. Bufalin induced ROS production and apoptotic cell death, demonstrated by Hoechst 33258 staining as well as flow cytometry analysis. Bax redistributed from cytosol to mitochondria from 12 to 48 h after bufalin treatment in living cells expressed with green fluorescent protein Bax. Treatment with the antioxidantN-acetyl-cysteine (NAC), a ROS scavenger, inhibited ROS generation and Bax translocation and led to a significant protection against bufalin-induced apoptosis. Our results also revealed that bufalin induced a prominent increase of caspase-3 activation blocked potently by NAC. Taken together, bufalin induced ROS-mediated Bax translocation, mitochondrial permeability transition and caspase-3 activation, implying that bufalin induced apoptosis via ROS-dependent mitochondrial death pathway in ASTC-a-1 cells.

scholarly journals Roles of Reactive Oxygen Species and Mitochondria in Seed Germination

2021 ◽  
Vol 12 ◽  
Author(s):  
Muhammad Awais Farooq ◽  
Xiaomeng Zhang ◽  
Muhammad Mubashar Zafar ◽  
Wei Ma ◽  
Jianjun Zhao
Keyword(s):  
Reactive Oxygen Species ◽  
Heat Shock ◽  
Seed Germination ◽  
Seed Dormancy ◽  
Energy Demand ◽  
Crop Production ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species

Seed germination is crucial for the life cycle of plants and maximum crop production. This critical developmental step is regulated by diverse endogenous [hormones, reactive oxygen species (ROS)] and exogenous (light, temperature) factors. Reactive oxygen species promote the release of seed dormancy by biomolecules oxidation, testa weakening and endosperm decay. Reactive oxygen species modulate metabolic and hormone signaling pathways that induce and maintain seed dormancy and germination. Endosperm provides nutrients and senses environmental signals to regulate the growth of the embryo by secreting timely signals. The growing energy demand of the developing embryo and endosperm is fulfilled by functional mitochondria. Mitochondrial matrix-localized heat shock protein GhHSP24.7 controls seed germination in a temperature-dependent manner. In this review, we summarize comprehensive view of biochemical and molecular mechanisms, which coordinately control seed germination. We also discuss that the accurate and optimized coordination of ROS, mitochondria, heat shock proteins is required to permit testa rupture and subsequent germination.

Reactive oxygen species and mitochondrial membrane potential are modulated during CDDP-induced apoptosis in EC-109 cellsThis paper is one of a selection of papers in this Special Issue, entitled International Symposium on Recent Advances in Molecular, Clinical, and Social Medicine, and has undergone the Journal's usual peer-review process.

2007 ◽  
Vol 85 (2) ◽  
pp. 265-271 ◽  
Author(s):  
Xu-Bin Jing ◽  
Xian-Bin Cai ◽  
Hui Hu ◽  
Su-Zuan Chen ◽  
Bin-Ming Chen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Peer Review Process ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Apoptotic Pathway ◽  
Highly Active ◽  
Inhibition Of Growth ◽  
Induced Apoptosis ◽  
Dose Dependent

cis-Diamminedichloroplatinum (CDDP), commonly know as cisplatin, is a well known DNA-damaging agent, which is highly active in suppressing the proliferation of tumor cells. However, it is not clear that CDDP can induce growth inhibition of esophagus cancer cells. Using the cell line EC-109 from the esophagus, we found that CDDP would induce apoptotic responses. The addition of CDDP to cells led to the inhibition of growth in a time- and dose-dependent manner. CDDP generated reactive oxygen species (ROSs) in cells, which brought about a reduction in the intracellular mitochondrial transmembrane potential (Δψm), leading to apoptosis. Our findings demonstrate that ROSs, and the resulting oxidative stress, play a pivotal role in apoptosis. Preincubation of EC-109 cells with the hydrogen-peroxide-scavenging enzyme catalase partially inhibited the following: (i) the production of ROS; (ii) the disruption of the Δψm; and (iii) apoptosis. These results indicate that the enhancement of the generation of ROS and the disruption of Δψm are events involved in the apoptotic pathway of EC-109 induced by CDDP.

scholarly journals Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid

2015 ◽  
Vol 291 (4) ◽  
pp. 1933-1947 ◽  
Author(s):  
Andrea Comba ◽  
Luciana L. Almada ◽  
Ezequiel J. Tolosa ◽  
Eriko Iguchi ◽  
David L. Marks ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Arachidonic Acid ◽  
Tumor Growth ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Down Regulation ◽  
Induced Apoptosis

Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4-1BB, in AA-treated cells. We demonstrated that down-regulation of the transcription factor glioma-associated protein 1 (GLI1) in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1, and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules and regulates their expression and promoter activity. We provide evidence that AA-induced apoptosis and down-regulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability, and expression of antiapoptotic molecules. Further characterization showed that AA represses GLI1 expression by stimulating nuclear translocation of NFATc1, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants impaired the AA-induced apoptosis and down-regulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for future PUFA-based therapeutic approaches.

scholarly journals Loss of p53 Sensitizes Cells to Palmitic Acid-Induced Apoptosis by Reactive Oxygen Species Accumulation

2019 ◽  
Vol 20 (24) ◽  
pp. 6268 ◽  
Author(s):  
Guowu Yu ◽  
Hongwei Luo ◽  
Na Zhang ◽  
Yongbin Wang ◽  
Yangping Li ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Palmitic Acid ◽  
Cell Line ◽  
Hct116 Cell ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Western Blots ◽  
Primary Mouse ◽  
Induced Apoptosis

Palmitic acid, the most common saturated free fatty acid, can lead to lipotoxicity and apoptosis when overloaded in non-fat cells. Palmitic acid accumulation can induce pancreatic β-cell dysfunction and cardiac myocyte apoptosis. Under various cellular stresses, the activation of p53 signaling can lead to cell cycle arrest, DNA repair, senescence, or apoptosis, depending on the severity/type of stress. Nonetheless, the precise role of p53 in lipotoxicity induced by palmitic acid is not clear. Here, our results show that palmitic acid induces p53 activation in a dose- and time-dependent manner. Furthermore, loss of p53 makes cells sensitive to palmitic acid-induced apoptosis. These results were demonstrated in human colon carcinoma cells (HCT116) and primary mouse embryo fibroblasts (MEF) through analysis of DNA fragmentation, flow cytometry, colony formation, and Western blots. In the HCT116 p53−/− cell line, palmitic acid induced greater reactive oxygen species formation compared to the p53+/+ cell line. The reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and reduced glutathione (GSH) partially attenuated apoptosis in the HCT116 p53−/− cell line but had no obvious effect on the p53+/+ cell line. Furthermore, p53 induced the expression of its downstream target genes, p21 and Sesn2, in response to ROS induced by palmitic acid. Loss of p21 also leads to more palmitic acid-induced cell apoptosis in the HCT116 cell line compared with HCT116 p53+/+ and HCT116 p53−/−. In a mouse model of obesity, glucose tolerance test assays showed higher glucose levels in p53−/− mice that received a high fat diet compared to wild type mice that received the same diet. There were no obvious differences between p53−/− and p53+/+ mice that received a regular diet. We conclude that p53 may provide some protection against palmitic acid- induced apoptosis in cells by targeting its downstream genes in response to this stress.

scholarly journals Zerumbone Promotes Cytotoxicity in Human Malignant Glioblastoma Cells through Reactive Oxygen Species (ROS) Generation

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Mohammad Jalili-Nik ◽  
Mohammad Montazami Sadeghi ◽  
Elmira Mohtashami ◽  
Hamid Mollazadeh ◽  
Amir R. Afshari ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Treatment Options ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Concentration Dependent Manner ◽  
Surgical Interventions ◽  
Induced Apoptosis

Glioblastoma multiforme (GBM) is the most hostile tumor in the central nervous system. Unfortunately, the prognosis of GBM patients is poor following surgical interventions, chemotherapy, and radiotherapy. Consequently, more efficient and effective treatment options for the treatment of GBM need to be explored. Zerumbone, as a sesquiterpene derived from Zingiber zerumbet Smith, has substantial cytotoxic and antiproliferative activities in some types of cancer. Here, we show that exposure of GBM cells (U-87 MG) to Zerumbone demonstrated significant growth inhibition in a concentration-dependent manner. Zerumbone also induced apoptosis and caused cell cycle arrest of human GBM U-87 MG cells in the G2/M phase of the cell cycle. In detail, the apoptotic process triggered by Zerumbone involved the upregulation of proapoptotic Bax and the suppression of antiapoptotic Bcl-2 genes expression as determined by qRT-PCR. Moreover, Zerumbone enhanced the generation of reactive oxygen species (ROS), and N-acetyl cysteine (NAC), as an antioxidant, reversed the ROS-induced cytotoxicity of U-87 MG cells. The Western blot analysis suggested that Zerumbone activated the NF-κB p65, which was partly inhibited by NAC treatment. Collectively, our results confirmed that Zerumbone induces cytotoxicity by ROS generation. Thus, the study raises the possibility of Zerumbone as a potential natural agent for treating GBM due to its ability to induce cytotoxicity.

Reactive Oxygen Species Are Necessary for Bleomycin A5-Induced Apoptosis and Extracellular Matrix Elimination of Nasal Polyp-Derived Fibroblasts

2018 ◽  
Vol 128 (2) ◽  
pp. 135-144
Author(s):  
Fan Wu ◽  
Peng Tian ◽  
Yun Ma ◽  
Jingyi Wang ◽  
Huashuang Ou ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Extracellular Matrix ◽  
Nasal Polyp ◽  
Reactive Oxygen ◽  
Growth Characteristics ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Ecm Degradation ◽  
Induced Apoptosis

Background: The pathology of chronic rhinosinusitis with nasal polyp (CRSwNP) is characterized by the infiltration of a large number of fibroblasts, resulting in extracellular matrix (ECM) deposition. Intralesional bleomycin A5 (BLE) injection has proved to be effective and safe, providing a novel treatment for CRSwNP. However, the mechanism is not clearly understood. Objectives: The aim of this study is to explore the possible mechanism of BLE-induced apoptosis in nasal polyp–derived fibroblasts (NPDFs). Material and methods: Dichloro-dihydro-fluorescein diacetate probe, cell migration assays, and cell cycle analysis were used to detect the growth characteristics and basal reactive oxygen species (ROS) traits of NPDFs. Annexin V/propidium iodide and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay was used to detect BLE-induced apoptosis. As a control, the antioxidant glutathione (GSH) was used to abrogate ROS induced by BLE. Western blot analysis was used to evaluate the effects of BLE on apoptosis and the ECM proteins of NPDFs. Results: The results showed that NPDFs had more active growth characteristics and higher basal ROS levels than normal nasal mucosa fibroblasts (NMFCs). NPDFs were more sensitive to BLE-induced apoptosis and ROS accumulation. GSH abrogation inhibits BLE-induced ECM degradation and apoptosis in NPDFs through a mitochondrial-mediated pathway. Conclusions: BLE induced NPDF apoptosis and ECM degradation through a mitochondrial-mediated pathway and in a ROS-dependent manner.

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