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Fujimoto S, Endo M, Tonomura S, Tsuji F, Haraguchi H, Hasegawa K, Numao T, Izumi A, Tourtas T, Schlötzer-Schrehardt U, Kruse F, Oyama Y, Ikawa M, Jun AS, Koizumi N, Okumura N. Therapeutic Potential of Emricasan, a Pan-Caspase Inhibitor, in Reducing Cell Death and Extracellular Matrix Accumulation in Fuchs Endothelial Corneal Dystrophy. Cells 2025; 14:498. [PMID: 40214452 PMCID: PMC11988121 DOI: 10.3390/cells14070498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 03/18/2025] [Accepted: 03/19/2025] [Indexed: 04/14/2025] Open
Abstract
Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by endothelial cell loss and excessive extracellular matrix (ECM) accumulation leading to corneal dysfunction. Emricasan, a pan-caspase inhibitor, was investigated for its therapeutic potential in suppressing these pathological changes. Patient-derived FECD cells and stress-induced cell models were treated with emricasan to assess its effects on apoptosis and ECM production. Caspase-specific knockdown experiments were performed to identify key mediators. Col8a2Q455K/Q455K mice, model mice of early-onset FECD, received twice-daily administration of 0.1% emricasan eye drops from 8 to 28 weeks of age. Endothelial cell density, hexagonality, cell size variation, and guttae area were evaluated by contact specular microscopy, while transcriptomic changes were analyzed via RNA sequencing. Emricasan effectively reduced apoptosis and ECM production in vitro by selectively inhibiting caspase-7 without affecting canonical TGF-β signaling. In vivo, emricasan-treated mice exhibited significantly higher endothelial cell density, improved hexagonality, and reduced variation in cell size compared with controls. Transcriptome analysis revealed distinct gene expression changes in the corneal endothelium following emricasan treatment. These findings suggest that emricasan exerts dual protective effects by inhibiting caspase-7-mediated ECM accumulation and broadly suppressing apoptosis, highlighting its potential as a pharmacological therapy for FECD.
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Affiliation(s)
- Sohya Fujimoto
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | - Mako Endo
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | - Shigehito Tonomura
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | - Fuuga Tsuji
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | - Hirotaka Haraguchi
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | - Kanna Hasegawa
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | - Taisuke Numao
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | | | - Theofilos Tourtas
- Department of Ophthalmology, University of Erlangen-Nürnberg, 430074 Erlangen, Germany
| | | | - Friedrich Kruse
- Department of Ophthalmology, University of Erlangen-Nürnberg, 430074 Erlangen, Germany
| | - Yuki Oyama
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
- Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
| | - Masahito Ikawa
- Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
| | - Albert S. Jun
- Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Noriko Koizumi
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
| | - Naoki Okumura
- Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 602-8580, Japan
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Zhao Q, Han B, Peng C, Zhang N, Huang W, He G, Li JL. A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents. Med Res Rev 2024; 44:2194-2235. [PMID: 38591229 DOI: 10.1002/med.22039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/10/2024]
Abstract
Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.
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Affiliation(s)
- Qian Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Dermatology & Venerolog, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Gu He
- Department of Dermatology & Venerolog, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jun-Long Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Anti-Infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, China
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Obeagu EI, Ubosi NI, Obeagu GU, Egba SI, Bluth MH. Understanding apoptosis in sickle cell anemia patients: Mechanisms and implications. Medicine (Baltimore) 2024; 103:e36898. [PMID: 38215146 PMCID: PMC10783340 DOI: 10.1097/md.0000000000036898] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 12/18/2023] [Indexed: 01/14/2024] Open
Abstract
Sickle cell anemia (SCA) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. While much research has focused on the molecular and cellular mechanisms underlying the pathophysiology of SCA, recent attention has turned to the role of apoptosis, or programmed cell death, in the disease progression. This review aims to elucidate the intricate mechanisms of apoptosis in SCA patients and explore its implications in disease severity, complications, and potential therapeutic interventions. Different research search engines such as PubMed central, Scopus, Web of Science, Google Scholar, ResearchGate, Academia Edu, etc were utilized in writing this paper. Apoptosis, a highly regulated cellular process, plays a crucial role in maintaining homeostasis by eliminating damaged or dysfunctional cells. In SCA, the imbalance between pro-apoptotic and anti-apoptotic signals contributes to increased erythrocyte apoptosis, exacerbating anemia and vaso-occlusive crises. Various factors, including oxidative stress, inflammation, and altered cell signaling pathways, converge to modulate the apoptotic response in SCA. Furthermore, the interaction between apoptotic cells and the vascular endothelium contributes to endothelial dysfunction, promoting the pathogenesis of vasculopathy and organ damage seen in SCA patients. In conclusion, unraveling the complexities of apoptosis in SCA provides valuable insights into the disease pathophysiology and offers novel avenues for therapeutic interventions.
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Affiliation(s)
| | - Nwanganga Ihuoma Ubosi
- Department of Public Health Sciences, Faculty of Health Sciences, National Open University of Nigeria, Headquarters, Jabi, Abuja, Nigeria
| | | | - Simeon Ikechukwu Egba
- Department of Biochemistry, Michael Okpara University of Agriculture, Umudike, Abia State, Nigeria
| | - Martin H. Bluth
- Department of Pathology, Division of Blood Transfusion Medicine, Maimonides Medical Center, Brooklyn, NY, USA
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Ying D, Shen X, Wang S, Chen J, Wu Z, Chen W, Wang F, Min J, Yu Y. Discovery of 4-hydroxyl pyrazole derivatives as potent ferroptosis inhibitors. Eur J Med Chem 2024; 263:115913. [PMID: 37950965 DOI: 10.1016/j.ejmech.2023.115913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/11/2023] [Accepted: 10/24/2023] [Indexed: 11/13/2023]
Abstract
Ferroptosis, an iron-dependent form of regulated cell death, has been well recognized as a pathogenic mechanism in driving many diseases, such as neurodegenerative disorders, ischemia-reperfusion (I/R) injury. Blocking ferroptosis has been emerging as a feasible therapeutic strategy for the prevention and treatment of these diseases. However, novel potent ferroptosis inhibitors remain to be developed for further clinical applications. In this study, we screened our in-house compound libraries by phenotypic assays and identified a 4-hydroxyl pyrazole derivative HW-3 with good ferroptosis inhibitory activity (EC50 = 120.1 ± 3.5 nM). Based on the structure of HW-3, a series of 4-hydroxyl pyrazole derivatives were further designed and synthesized. Among these compounds, compound 25 could significantly inhibit RSL3-induced ferroptosis with an EC50 value of 8.6 ± 2.2 nM in HT-1080 cells, which was 3-fold more potent than the classical ferroptosis inhibitor ferrostatin-1 (Fer-1) (EC50 = 23.4 ± 1.3 nM). The potent ferroptosis inhibitory activity of compound 25 was further validated in multiple additional cell lines. Our mechanistic study revealed that compound 25 inhibited ferroptosis via intrinsic radical-trapping antioxidative capacity. Taken together, the findings of our study demonstrate 4-hydroxyl pyrazole derivative 25 is a potent ferroptosis inhibitor, which holds a great therapeutic potential for further development.
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Affiliation(s)
- Danzhi Ying
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xin Shen
- The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Shuqi Wang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Junyi Chen
- The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Zhenying Wu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wenteng Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Fudi Wang
- The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Junxia Min
- The First Affiliated Hospital, The Second Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Yongping Yu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Ren R, Li Y. STIM1 in tumor cell death: angel or devil? Cell Death Discov 2023; 9:408. [PMID: 37932320 PMCID: PMC10628139 DOI: 10.1038/s41420-023-01703-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 10/21/2023] [Accepted: 10/27/2023] [Indexed: 11/08/2023] Open
Abstract
Stromal interaction molecule 1 (STIM1) is involved in mediating the store-operated Ca2+ entry (SOCE), driving the influx of the intracellular second messenger calcium ion (Ca2+), which is closely associated with tumor cell proliferation, metastasis, apoptosis, autophagy, metabolism and immune processes. STIM1 is not only regulated at the transcriptional level by NF-κB and HIF-1, but also post-transcriptionally modified by miRNAs and degraded by ubiquitination. Recent studies have shown that STIM1 or Ca2+ signaling can regulate apoptosis, autophagy, pyroptosis, and ferroptosis in tumor cells and act discrepantly in different cancers. Furthermore, STIM1 contributes to resistance against antitumor therapy by influencing tumor cell death. Further investigation into the mechanisms through which STIM1 controls other forms of tumor cell death could aid in the discovery of novel therapeutic targets. Moreover, STIM1 has the ability to regulate immune cells within the tumor microenvironment. Here, we review the basic structure, function and regulation of STIM1, summarize the signaling pathways through which STIM1 regulates tumor cell death, and propose the prospects of antitumor therapy by targeting STIM1.
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Affiliation(s)
- Ran Ren
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, 400044, Chongqing, China
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, 400044, Chongqing, China.
- Department of Medical Oncology, Chongqing University Cancer Hospital, 400030, Chongqing, China.
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Zhao Y, Wang S, Pan J, Ma K. Verbascoside: A neuroprotective phenylethanoid glycosides with anti-depressive properties. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 120:155027. [PMID: 37657207 DOI: 10.1016/j.phymed.2023.155027] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/31/2023] [Accepted: 08/14/2023] [Indexed: 09/03/2023]
Abstract
BACKGROUND Verbascoside is a natural and water-soluble phenylethanoid glycoside found in several medicinal plants. It has extensive pharmacological effects, including antioxidative and antineoplastic actions, and a wide range of therapeutic effects against depression. PURPOSE In this review, we appraised preclinical and limited clinical evidence to fully discuss the anti-depression capacity of verbascoside and its holistic characteristics that can contribute to better management of depression in vivo and in vitro models, as well as, its toxicities and medicinal value. METHODS This review was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A systematic review of 32 preclinical trials published up to April 2023, combined with a comprehensive bioinformatics analysis of network pharmacology and molecular docking, was conducted to elucidate the antidepressant mechanism of action of verbascoside. Studies included in the systematic review were obtained from 7 electronic databases: PubMed, Scopus, Web of Science, Cochrane, ResearchGate, ScienceDirect, and Google Scholar. RESULTS Studies on the antidepressant effects of verbascoside showed that various pharmacological mechanisms and pathways, such as modulating the levels of monoamine neurotransmitters, inhibiting hypothalamic-pituitary-adrenal (HPA) axis hyperfunction and promoting neuroprotection may be involved in the process of its action against depression. Verbascoside promotes dopamine (DA) biosynthesis by promoting the expression of tyrosine hydroxylase mRNA and protein, upregulates the expression of 5-hydroxytryptamine receptor 1B (5-HT1B), prominence protein, microtubule-associated protein 2 (MAP2), hemeoxygenase-1 (HO-1), SQSTM1, Recombinant Autophagy Related Protein 5 (ATG5) and Beclin-1, and decreases the expression of caspase-3 and a-synuclein, thus exerting antidepressant effects. We identified seven targets (CCL2, FOS, GABARAPL1, CA9, TYR, CA12, and SQSTM1) and three signaling pathways (glutathione metabolism, metabolism of xenobiotics by cytochrome P450, fluid shear stress and atherosclerosis) as potential molecular biological sites for verbascoside. CONCLUSIONS These findings provide strong evidence that verbascoside exerts its antidepressant effects through various pharmacological mechanisms. However, further multicentre clinical case-control and molecularly targeted fishing studies are required to confirm the clinical efficacy of verbascoside and its underlying direct targets.
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Affiliation(s)
- Yi Zhao
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Sijia Wang
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Jin Pan
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Ke Ma
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
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Jiang X, Teng X, Shi H, Cao L, He L, Gu Q. Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors. Bioorg Chem 2023; 133:106393. [PMID: 36731296 DOI: 10.1016/j.bioorg.2023.106393] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/25/2023]
Abstract
Ferroptosis is a new type of cell death associated with many human diseases. It is a new strategy to discover ferroptosis inhibitors for the treatment of ferroptosis-related diseases. Here the FDA-approved drug library containing 1160 molecules was screened for ferroptosis inhibitors in RSL3-induced HT22 mouse hippocampal neuronal cells. As a result, olanzapine showed potent ferroptosis inhibitory activity (EC50 = 1.18 μM). Structural optimization and the structure-activity relationships (SARs) analysis led to the synthesis of 41 new derivatives (4-44) and one known compound 45. Comparing with olanzapine, its derivative 36 showed nearly sixteen-folds improved ferroptosis inhibition and low cytotoxicity (EC50 = 0.074 μM, CC50 = 18.8 μM). Further mechanistic studies revealed that compound 36 specifically inhibited ferroptosis by its antioxidative ability. This work demonstrates that olanzapine protected RSL3-induced ferroptosis in HT22 cell, and its derivative 36 having nanomolar ferroptosis inhibitory activity merit to be developed for drugs against ferroptosis-related neurological diseases.
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Affiliation(s)
- Xiufen Jiang
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China; Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China
| | - Xifeng Teng
- Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China; Key Laboratory of Lingnan Medicinal Materials Production and Development, National Administration of Traditional Chinese Medicine, Guangzhou 510006, People's Republic of China
| | - Huiwen Shi
- Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China
| | - Liudan Cao
- Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China
| | - Lin He
- Guangdong Pharmaceutical University, Guangzhou 510006, People's Republic of China; Guangdong Provincial Engineering and Technology Research Center of Cosmetics, Guangdong Pharmaceutical University, Zhongshan 528458, People's Republic of China.
| | - Qiong Gu
- Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
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Sharmin S, Rahaman MM, Martorell M, Sastre-Serra J, Sharifi-Rad J, Butnariu M, Bagiu IC, Bagiu RV, Islam MT. Cytotoxicity of synthetic derivatives against breast cancer and multi-drug resistant breast cancer cell lines: a literature-based perspective study. Cancer Cell Int 2021; 21:612. [PMID: 34801046 PMCID: PMC8606078 DOI: 10.1186/s12935-021-02309-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/31/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer is the second most killer worldwide causing millions of people to lose their lives every year. In the case of women, breast cancer takes away the highest proportion of mortality rate than other cancers. Due to the mutation and resistance-building capacity of different breast cancer cell lines against conventional therapies, this death rate is on the verge of growth. New effective therapeutic compounds and treatment method is the best way to look out for in this critical time. For instance, new synthetic derivatives/ analogues synthesized from different compounds can be a ray of hope. Numerous synthetic compounds have been seen enhancing the apoptosis and autophagic pathway that directly exerts cytotoxicity towards different breast cancer cell lines. To cease the ever-growing resistance of multi-drug resistant cells against anti-breast cancer drugs (Doxorubicin, verapamil, tamoxifen) synthetic compounds may play a vital role by increasing effectivity, showing synergistic action. Many recent and previous studies have reported that synthetic derivatives hold potentials as an effective anti-breast cancer agent as they show great cytotoxicity towards cancer cells, thus can be used even vastly in the future in the field of breast cancer treatment. This review aims to identify the anti-breast cancer properties of several synthetic derivatives against different breast cancer and multi-drug-resistant breast cancer cell lines with their reported mechanism of action and effectivity.
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Affiliation(s)
- Shabnam Sharmin
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj (Dhaka), 8100, Bangladesh
| | - Md Mizanur Rahaman
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj (Dhaka), 8100, Bangladesh
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, 4070386, Concepción, Chile
| | - Jorge Sastre-Serra
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de La Salut (IUNICS), Universitat de Les Illes Balears, Palma de Mallorca, Illes Balears, Spain.,Instituto de Investigación Sanitaria de Las Islas Baleares (IdISBa), Hospital Universitario Son Espases, Edificio S, 07120, Palma de Mallorca, Illes Balears, Spain.,Ciber Fisiopatología Obesidad y Nutrición (CB06/03), Instituto Salud Carlos III, 28029, Madrid, Spain
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Monica Butnariu
- Banat's University of Agricultural Sciences and Veterinary Medicine "King Michael I of Romania" From Timisoara, Timisoara, Romania.
| | - Iulia Cristina Bagiu
- Department of Microbiology, Victor Babes University of Medicine and Pharmacy of Timisoara, Timisoara, Romania.,Multidisciplinary Research Center On Antimicrobial Resistance, Timisoara, Romania
| | - Radu Vasile Bagiu
- Department of Microbiology, Victor Babes University of Medicine and Pharmacy of Timisoara, Timisoara, Romania.,Preventive Medicine Study Center, Timisoara, Romania
| | - Mohammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj (Dhaka), 8100, Bangladesh
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Fusco A, Savio V, Donniacuo M, Perfetto B, Donnarumma G. Antimicrobial Peptides Human Beta-Defensin-2 and -3 Protect the Gut During Candida albicans Infections Enhancing the Intestinal Barrier Integrity: In Vitro Study. Front Cell Infect Microbiol 2021; 11:666900. [PMID: 34178720 PMCID: PMC8223513 DOI: 10.3389/fcimb.2021.666900] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 05/17/2021] [Indexed: 12/24/2022] Open
Abstract
The intestinal mucosa is composed of a monolayer of epithelial cells, which is highly polarized and firmly united to each other thanks to the presence of proteins complexes, called Tight junctions (TJs). Alteration of the mucus layer and TJs causes an increase in intestinal permeability, which can lead to a microbial translocation and systemic disorders. Candida albicans, in addition to its role of commensal, is an opportunistic pathogen responsible for disseminated candidiasis, especially in immunocompromised subjects where the dysbiosis leads to damage of the intestinal mucosal barrier . In this work, we used a line of intestinal epithelial cells able to stably express the genes that encodes human beta defensin-2 (HBD-2) and -3 (HBD-3) to monitor the invasion of C. albicans in vitro. Defensins are a group of antimicrobial peptides (AMPs) found in different living organisms, and are involved in the first line of defense in the innate immune response against pathogens. The results obtained show that the presence of antimicrobial peptides improves the expression of TJs and increases the Trans Epithelial Electrical Resistence value. In addition, the invasive ability of C. albicans in transfected cells is significantly reduced, as well as the expression levels of genes involved in the apoptotic pathway. Through the study of interaction between antimicrobial peptides and microbiota we will be able in the future to better understand the mechanisms by which they exert the host defense function against intestinal pathogens.
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Affiliation(s)
- Alessandra Fusco
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Vittoria Savio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Donniacuo
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Brunella Perfetto
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giovanna Donnarumma
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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Yang X, Xue P, Chen H, Yuan M, Kang Y, Duscher D, Machens HG, Chen Z. Denervation drives skeletal muscle atrophy and induces mitochondrial dysfunction, mitophagy and apoptosis via miR-142a-5p/MFN1 axis. Theranostics 2020; 10:1415-1432. [PMID: 31938072 PMCID: PMC6956801 DOI: 10.7150/thno.40857] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 11/17/2019] [Indexed: 02/06/2023] Open
Abstract
Rationale: Peripheral nerve injury is common in clinic, which leads to severe atrophy and dysfunction of the denervated muscles, but the underlying mechanism is not fully understood. Recent studies advanced the causative role of mitochondrial dysfunction in muscle atrophy, while the upstream triggers remained unclear. Methods: In the present study, Atrophy of gastrocnemius and tibialis anterior (TA) were evaluated in mice sciatic nerve transection model. Transmission electron microscopy (TEM) was then used to observe the microstructure of atrophic gastrocnemius and mitochondria. Subsequently, small RNA sequencing, luciferase reporter assay and Electrophoretic Mobility Shift (EMSA) were performed to explore the potential signaling pathway involved in skeletal muscle atrophy. The effects of the corresponding pathway on mitochondrial function, mitophagy, apoptosis and muscle atrophy were further determined in C2C12 cells and denervated gastrocnemius. Results: Gastrocnemius and TA atrophied rapidly after denervation. Obvious decrease of mitochondria number and activation of mitophagy was further observed in atrophic gastrocnemius. Further, miR-142a-5p/ mitofusin-1 (MFN1) axis was confirmed to be activated in denervated gastrocnemius, which disrupted the tubular mitochondrial network, and induced mitochondrial dysfunction, mitophagy and apoptosis. Furthermore, the atrophy of gastrocnemius induced by denervation was relieved through targeting miR-142a-5p/MFN1 axis. Conclusions: Collectively, our data revealed that miR-142a-5p was able to function as an important regulator of denervation-induced skeletal muscle atrophy by inducing mitochondrial dysfunction, mitophagy, and apoptosis via targeting MFN1. Our findings provide new insights into the mechanism of skeletal muscle atrophy following denervation and propose a viable target for therapeutic intervention in individuals suffering from muscle atrophy after peripheral nerve injury.
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11
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Tripathi N, Vetrivel I, Téletchéa S, Jean M, Legembre P, Laurent AD. Investigation of Phospholipase Cγ1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors. Int J Mol Sci 2019; 20:4721. [PMID: 31548507 PMCID: PMC6801593 DOI: 10.3390/ijms20194721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/17/2019] [Accepted: 09/19/2019] [Indexed: 01/03/2023] Open
Abstract
The enzyme phospholipase C gamma 1 (PLCγ1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLCγ1. Therefore, for the first time, a combination of various biophysical methods has been employed to shed light on the atomistic interactions between PLCγ1 and its known binding partners. Indeed, molecular modeling of PLCγ1 with SLP76 peptide and with previously reported inhibitors (ritonavir, anethole, daunorubicin, diflunisal, and rosiglitazone) facilitated the identification of the common critical residues (Gln805, Arg806, Asp808, Glu809, Asp825, Gly827, and Trp828) as well as the quantification of their interaction through binding energies calculations. These features are in agreement with previous experimental data. Such an in depth biophysical analysis of each complex provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular docking and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising inhibitors, all characterized by a strong binding with PLCγ1 and a comparable or higher binding affinity to ritonavir (∆Gbind < -25 kcal/mol), one of the most potent inhibitor reported till now.
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Affiliation(s)
- Neha Tripathi
- CEISAM UMR CNRS 6230, UFR Sciences et Techniques, Université de Nantes, 44322 Nantes CEDEX 3, France.
| | - Iyanar Vetrivel
- CEISAM UMR CNRS 6230, UFR Sciences et Techniques, Université de Nantes, 44322 Nantes CEDEX 3, France.
| | - Stéphane Téletchéa
- UFIP UMR CNRS 6286, UFR Sciences et Techniques, Université de Nantes, 44322 Nantes CEDEX 3, France.
| | - Mickaël Jean
- CLCC Eugène Marquis, Equipe Ligue Contre Le Cancer, 35042 Rennes, France.
| | - Patrick Legembre
- CLCC Eugène Marquis, Equipe Ligue Contre Le Cancer, 35042 Rennes, France.
- COSS INSERM UMR1242, Université Rennes 1, 35042 Rennes, France.
| | - Adèle D Laurent
- CEISAM UMR CNRS 6230, UFR Sciences et Techniques, Université de Nantes, 44322 Nantes CEDEX 3, France.
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12
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Zhang Y, Zhang Q, Xin W, Liu N, Zhang H. Nudol, a phenanthrene derivative from Dendrobium nobile, induces cell cycle arrest and apoptosis and inhibits migration in osteosarcoma cells. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:2591-2601. [PMID: 31551653 PMCID: PMC6677380 DOI: 10.2147/dddt.s180610] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 06/10/2019] [Indexed: 01/08/2023]
Abstract
Purpose: Osteosarcoma is the most common malignancy of the bone in children and adolescents. There is an urgent need for the development of novel drugs to treat it. Nudol(1), a phenanthrene compound from the traditional Chinese medicine, Dendrobium nobile, exhibited antiproliferative activity against osteosarcoma cells. Therefore, the aim of the present study was to investigate the role and underlying mechanism of nudol(1) as potential chemotherapy for osteosarcoma. Methods: Cell viability was determined by MTT assay. Cell-cycle phase distribution was analyzed by flow cytometry and Western blot. DAPI staining was used for morphology observation. Apoptosis was analysis via flow cytometry. The expression levels of mRNA and protein related to capase-mediated apoptotic pathway were detected by real-time PCR and western blotting. Migration was determined by wound healing assays. Results: Nudol(1) significantly decreased cell viability in several cancer cell lines. Moreover, nudol(1) caused cell cycle arrest at G2/M phase in U2OS cells, and it also induced cell apoptosis through the caspase-dependent pathway. In addition, treatment with nudol(1) suppressed the migration of U2OS cells. Conclusion: The present study, for the first time, demonstrated effects of nudol(1) on OS in vitro and the potential molecular mechanisms. Accordingly, nudol(1) might have the potential for further development as a lead compound against bone tumor.
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Affiliation(s)
- Yuying Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, People's Republic of China
| | - Qianqian Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, People's Republic of China
| | - Wei Xin
- Central Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, People's Republic of China
| | - Na Liu
- School of Biological Science and Technology, University of Jinan, Jinan, People's Republic of China
| | - Hua Zhang
- School of Biological Science and Technology, University of Jinan, Jinan, People's Republic of China
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13
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Cong H, Xu L, Wu Y, Qu Z, Bian T, Zhang W, Xing C, Zhuang C. Inhibitor of Apoptosis Protein (IAP) Antagonists in Anticancer Agent Discovery: Current Status and Perspectives. J Med Chem 2019; 62:5750-5772. [DOI: 10.1021/acs.jmedchem.8b01668] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Hui Cong
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Lijuan Xu
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Yougen Wu
- College of Tropical Agriculture and Forestry, Hainan University, 58 Renmin Avenue, Haikou 570228, China
- Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
| | - Zhuo Qu
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
| | - Tengfei Bian
- Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
| | - Wannian Zhang
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
| | - Chengguo Xing
- Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, Florida 32610, United States
| | - Chunlin Zhuang
- School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China
- School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
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14
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Saghazadeh A, Ferrari CC, Rezaei N. Deciphering variability in the role of interleukin-1β in Parkinson's disease. Rev Neurosci 2018; 27:635-50. [PMID: 27166719 DOI: 10.1515/revneuro-2015-0059] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 04/01/2016] [Indexed: 12/16/2022]
Abstract
Although the role of inflammation in neurodegeneration has been well acknowledged, less is known on the issue of each cytokine in specific neurodegenerative diseases. In this review, we will present evidence elucidating that interleukin-1β (IL-1β) has a multi-faceted character in pathogenesis of Parkinson's disease, which is a progressive neurodegenerative disorder. Increased levels of IL-1β were found in PD patients. Besides, PD symptoms were observed in IL-1β wild-type, but not deficient, animals. These lines of evidence suggest that IL-1β may contribute to the initiation or progression of PD. On the other hand, some studies reported decreased levels of IL-1β in PD patients. Also, genetic studies provided evidence suggesting that IL-1β may protect individuals against PD. Presumably, the broad range of IL-1β role is due to its interaction with both upstream and downstream mediators. Differences in IL-1β levels could be because of glia population (i.e. microglia and astrocytes), mitogen-activated protein kinase and nuclear factor κ light-chain-enhancer of activated B cells signaling pathways, and several mediators (including cyclooxygenase, neurotrophic factors, reactive oxygen species, caspases, heme oxygenase-1, and matrix metalloproteinases). Although far from practice at this point, unraveling theoretical therapeutic targets based on the up-down IL-1β neuroweb could facilitate the development of strategies that are likely to be used for pharmaceutical designs of anti-neurodegenerative drugs of the future.
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15
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Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2017. [PMID: 27570424 DOI: 10.3748/wjg.vss.i30.6876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
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Affiliation(s)
- Tao Hu
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Zhen Li
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Chun-Ying Gao
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Chi Hin Cho
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
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16
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Tokarz-Deptuła B, Hukowska-Szematowicz B, Niedźwiedzka-Rystwej P, Trzeciak-Ryczek A, Deptuła W. Values of apoptosis of lymphocytes and granulocytes in peripheral blood of Polish mixed-breed rabbits in the annual cycle. Pol J Vet Sci 2017; 20:37-43. [PMID: 28525323 DOI: 10.1515/pjvs-2017-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The objective of the study was to determine values of apoptosis for peripheral blood lymphocytes and granulocytes, including dependency on the season of the year, in Polish mixed-breed rabbits and in mixed-breed rabbits with the addition of blood of meat-breed rabbits. The study was carried out in four seasons of the year (spring, summer, autumn, winter) involving 120 Polish mixed-breed rabbits - group I, and 120 Polish mixed-breed rabbits with addition of meat-breed rabbit blood - group II. Assessment of apoptosis of lymphocytes and granulocytes was performed using as FACScan cytometer by Becton Dickinson with FACSDiva software (USA), using as ApoFluor® Green Caspase reagent kit (MP Biomedicals, USA) to detect the activity of the total caspase pool 1, 3, 4, 5, 6, 7, 8, 9 in granulocytes and lymphocytes of rabbit peripheral blood. The results for apoptosis of lymphocytes and granulocytes in peripheral blood in the animals investigated (group I and II) were subjected to statistical analysis with the t'Student test at p=0.05. It was noted that, in rabbits from group I, the values for apoptosis of lymphocytes were the highest in winter and autumn (36.02% and 31.24%, respectively), and the lowest in spring and summer (26.73% and 22.72%, respectively), whereas in the case of granulocytes the highest values were in summer and spring (14.69% and 12.95%, respectively), and the lowest in winter and autumn (8.16% and 8.57%, respectively). In mixed-breed rabbits with the addition of meat-breed blood (group II), the values for apoptosis of lympocytes were the highest in spring (29.13%), and the lowest in summer (25.43%); whereas in the case of granulocytes the highest values were in summer and spring (14.0% and 11.15%, respectively), and the lowest in autumn and winter (7.46% and 7.64%, respectively).
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17
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Zhang L, Fang Y, Xu XF, Jin DY. Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway. Mol Med Rep 2017; 15:1195-1203. [PMID: 28138710 PMCID: PMC5367346 DOI: 10.3892/mmr.2017.6144] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 10/24/2016] [Indexed: 01/01/2023] Open
Abstract
Moscatilin is a bibenzyl derivative extracted from the Dendrobium aurantiacum var. denneanum, which has traditionally been used as an immunomodulatory treatment in China. The present study was designed to determine whether moscatilin is a pro‑apoptotic agent in pancreatic cancer, and to elucidate the underlying mechanisms. The apoptotic and anti‑proliferative effects of moscatilin on pancreatic cancer cells were determined in vitro using biochemical assays, such as the MTT assay, colony formation assay, Hoechst staining and DNA fragmentation assay, and in vivo using Panc‑1 pancreatic cancer xenografts. Western blotting was also conducted to evaluate the expression levels of B‑cell lymphoma 2 (Bcl2), Bcl2‑associated X protein (Bax), Bcl2 homologous antagonist killer (Bak), caspase 3, cleaved‑caspase 3, poly (ADP‑ribose) polymerase, p‑c‑Jun N‑terminal kinase (JNK)/stress‑activated protein kinases (SAPK) and JNK/SAPK in response to moscatilin. We used DCFH‑DA to detect the production of reactive oxygen species (ROS) induced by moscatilin. The present study demonstrated that moscatilin markedly inhibited pancreatic cancer cell viability and induced cell apoptosis in a concentration‑dependent manner. Conversely, moscatilin did not affect the cell viability of human umbilical vein endothelial cells at the comparable dosage. Treatment with moscatilin suppressed clonogenicity of Panc‑1 cells in a concentration‑dependent manner. Furthermore, a decrease in Bcl2 expression, and an increase in the expression levels of Bak and Bax, was detected following treatment with moscatilin, resulting in an increase in the proapoptotic/anti‑apoptotic expression ratio (Bax/Bcl2) in Panc‑1 cells. Moscatilin also induced activation of the caspase‑dependent mitochondrial apoptotic pathway. In addition, moscatilin enhanced cellular ROS production and induced activation of JNKSAPK signaling pathway. Conversely, pretreatment with the ROS scavenger N‑acetylcysteine or the JNK/SAPK‑specific inhibitor SP600125 prevented moscatilin‑mediated reductions in cell viability. Furthermore, moscatilin inhibited tumor growth in nude mice bearing Panc‑1 cells, without apparent toxicity. In conclusion, these results demonstrated that moscatilin may induce pancreatic cell apoptosis, and therefore may be considered a potential therapeutic agent for the treatment of pancreatic cancer.
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Affiliation(s)
- Lei Zhang
- Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China
| | - Yuan Fang
- Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China
| | - Xue-Feng Xu
- Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China
| | - Da-Yong Jin
- Pancreatic Cancer Group, General Surgery Department, Zhongshan Hospital, Fudan University, Shanghai 200232, P.R. China
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18
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Mahdavi M, Dianat S, Khavari B, Moghimi S, Abdollahi M, Safavi M, Mouradzadegun A, Kabudanian Ardestani S, Sabourian R, Emami S, Akbarzadeh T, Shafiee A, Foroumadi A. Synthesis and biological evaluation of novel imidazopyrimidin-3-amines as anticancer agents. Chem Biol Drug Des 2016; 89:797-805. [DOI: 10.1111/cbdd.12904] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 10/08/2016] [Accepted: 10/31/2016] [Indexed: 11/28/2022]
Affiliation(s)
- Mohammad Mahdavi
- Drug Design and Development Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Shima Dianat
- Department of Chemistry; Faculty of Sciences; Shahid Chamran University; Ahvaz Iran
| | - Behnaz Khavari
- Institute of Biochemistry and Biophysics; Department of Biochemistry; University of Tehran; Tehran Iran
| | - Setareh Moghimi
- Department of Medicinal Chemistry; Faculty of Pharmacy and Pharmaceutical Sciences Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology; Faculty of Pharmacy and Pharmaceutical Sciences Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Maliheh Safavi
- Department of Biotechnology; Iranian Research Organization for Science and Technology; Tehran Iran
| | - Arash Mouradzadegun
- Department of Chemistry; Faculty of Sciences; Shahid Chamran University; Ahvaz Iran
| | | | - Reyhaneh Sabourian
- Persian Medicine and Pharmacy Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Saeed Emami
- Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center; Faculty of Pharmacy; Mazandaran University of Medical Sciences; Sari Iran
| | - Tahmineh Akbarzadeh
- Department of Medicinal Chemistry; Faculty of Pharmacy and Pharmaceutical Sciences Research Center; Tehran University of Medical Sciences; Tehran Iran
- Persian Medicine and Pharmacy Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Abbas Shafiee
- Department of Medicinal Chemistry; Faculty of Pharmacy and Pharmaceutical Sciences Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Alireza Foroumadi
- Drug Design and Development Research Center; Tehran University of Medical Sciences; Tehran Iran
- Department of Medicinal Chemistry; Faculty of Pharmacy and Pharmaceutical Sciences Research Center; Tehran University of Medical Sciences; Tehran Iran
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19
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Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis. Sci Rep 2016; 6:31441. [PMID: 27511630 PMCID: PMC4980610 DOI: 10.1038/srep31441] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 07/20/2016] [Indexed: 11/08/2022] Open
Abstract
Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response.
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20
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Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9(10H)-acridinone-1,2,3-triazoles. Mol Divers 2015; 19:787-95. [DOI: 10.1007/s11030-015-9616-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 07/01/2015] [Indexed: 10/23/2022]
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21
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Shen K, Xie J, Wang H, Zhang H, Yu M, Lu F, Tan H, Xu H. Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells. Mol Cancer Ther 2015; 14:1738-1749. [PMID: 25976678 DOI: 10.1158/1535-7163.mct-14-1048] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 05/07/2015] [Indexed: 11/16/2022]
Abstract
Cambogin is a polycyclic polyprenylated acylphoroglucinol (PPAP) from the Garcinia genus, which has been used traditionally for cancer treatment across Southeastern Asia. In this study, we found that cambogin inhibited breast cancer cell proliferation and induced cell apoptosis in vitro. Cambogin induced the activation of the caspase-independent mitochondrial apoptotic pathway, as indicated by an increase in the ratio of Bax/Bcl-2 and the nuclear translocation of apoptosis inducing factor (AIF). Two-dimensional gel electrophoresis and mass spectrometry revealed that the expression of proteins involving in the radical oxygen species (ROS) pathway was among the most affected upon cambogin treatment. Cambogin enhanced cellular ROS production, and induced the activation of the ASK1-MKK4/MKK7-JNK/SAPK signaling pathway. Pretreatment with ROS scavenger N-acetylcysteine (NAC), an antioxidant, or the JNK inhibitor SP600125 was able to restore cell viability in the presence of cambogin. Importantly, cambogin treatment led to the activation of activating transcription factor-2 (ATF-2) and the trimethylation of histone H3K9 in the activator protein 1 (AP-1) binding region of the Bcl-2 gene promoter. Finally, cambogin exhibited a potential antitumor effect in MCF-7 breast cancer xenografts without apparent toxicity. Taken in conjunction, the present study indicates that cambogin can induce breast adenocarcinoma cell apoptosis and therefore represents therapeutic potential for cancer treatment.
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Affiliation(s)
- Kaikai Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianling Xie
- South Australian Health & Medical Research Institute, North Terrace, Adelaide, Australia. Centre for Biological Sciences, Life Science Building, University of Southampton, Southampton, United Kingdom
| | - Hua Wang
- Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Hong Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengyuan Yu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fangfang Lu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongsheng Tan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongxi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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22
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Hird AW, Aquila BM, Hennessy EJ, Vasbinder MM, Yang B. Small molecule inhibitor of apoptosis proteins antagonists: a patent review. Expert Opin Ther Pat 2015; 25:755-74. [PMID: 25980951 DOI: 10.1517/13543776.2015.1041922] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins. AREAS COVERED This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists. EXPERT OPINION In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space - for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles - tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.
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Affiliation(s)
- Alexander W Hird
- AstraZeneca, Medicinal Chemistry, Oncology iMed , 35 Gatehouse Drive, Waltham, MA 02451 , USA +1 781 839 4145 ;
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23
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Synthesis, in vitro cytotoxicity and apoptosis inducing study of 2-aryl-3-nitro-2H-chromene derivatives as potent anti-breast cancer agents. Eur J Med Chem 2014; 86:562-9. [DOI: 10.1016/j.ejmech.2014.09.017] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 08/18/2014] [Accepted: 09/05/2014] [Indexed: 11/22/2022]
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24
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Samaga KKL, Rao GV, Chandrashekara Reddy G, Kush AK, Diwakar L. Synthetic racemates of abyssinone I and II induces apoptosis through mitochondrial pathway in human cervix carcinoma cells. Bioorg Chem 2014; 56:54-61. [PMID: 25019692 DOI: 10.1016/j.bioorg.2014.06.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 06/05/2014] [Accepted: 06/09/2014] [Indexed: 01/15/2023]
Abstract
Abyssinones I and II are prenylated flavanones existing in plant Erythrina abyssinica showing diverse biological activities including anticancer activities. We synthesized racemic mixtures of these flavanones from corresponding chalcones and herein we report for the first time the molecular mechanisms of cell death, anti-proliferative effect and ability to induce apoptosis in human cervical carcinoma (HeLa) cells. Cytotoxicity was assessed by MTT assay to determine LD50 for prenylated chalcones and their corresponding flavones. Abyssinones promoted apoptosis by up regulation of p53 and Bax, along with down regulation of Bcl-2. Apoptosis induction was mediated through mitochondrial pathway releasing cytochrome c and Apaf-1 into cytosol; associated with activation of caspase-3. Further they were able to decrease the expression of cell proliferation markers PCNA and cyclin D1 indicating anti proliferative activity. These observations demonstrate that abyssinones trigger apoptosis via mitochondrial pathway by activation of caspase-3 and disrupts cell cycle.
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Affiliation(s)
- Krishna Kumar L Samaga
- Department of Biological Sciences, Vittal Mallya Scientific Research Foundation, BTM II Stage, Bangalore 560076, India
| | | | - G Chandrashekara Reddy
- Chemistry Division, Vittal Mallya Scientific Research Foundation, BTM II Stage, Bangalore 560076, India
| | - Anil Kumar Kush
- Department of Biological Sciences, Vittal Mallya Scientific Research Foundation, BTM II Stage, Bangalore 560076, India
| | - Latha Diwakar
- Department of Biological Sciences, Vittal Mallya Scientific Research Foundation, BTM II Stage, Bangalore 560076, India.
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25
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Virzì GM, Clementi A, Brocca A, de Cal M, Vescovo G, Granata A, Ronco C. The hemodynamic and nonhemodynamic crosstalk in cardiorenal syndrome type 1. Cardiorenal Med 2014; 4:103-12. [PMID: 25254032 DOI: 10.1159/000362650] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 04/01/2014] [Indexed: 01/25/2023] Open
Abstract
The organ crosstalk can be defined as the complex biological communication and feedback between distant organs mediated via cellular, molecular, neural, endocrine and paracrine factors. In the normal state, this crosstalk helps to maintain homeostasis and optimal functioning of the human body. However, during disease states this very crosstalk can carry over the influence of the diseased organ to initiate and perpetuate structural and functional dysfunction in the other organs. Heart performance and kidney function are intimately interconnected, and the communication between these organs occurs through a variety of bidirectional pathways. The cardiorenal syndrome (CRS) is defined as a complex pathophysiological disorder of the heart and the kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. In particular, CRS type 1 is characterized by a rapid worsening of the cardiac function leading to acute kidney injury. This clinical condition requires a more complex management given its more complicated hospital course and higher mortality. A lot of research has emerged in the last years trying to explain the pathophysiology of CRS type 1 which remains in part poorly understood. This review primarily focuses on the hemodynamic and nonhemodynamic mechanisms involved in this syndrome.
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Affiliation(s)
- Grazia Maria Virzì
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Agrigento, Italy ; Department of IRRIV-International Renal Research Institute, Vicenza, Agrigento, Italy ; Department of Clinical Genetics Unit, Department of Women's and Children's Health, University of Padua, Padua, Agrigento, Italy
| | - Anna Clementi
- Department of IRRIV-International Renal Research Institute, Vicenza, Agrigento, Italy ; Department of Nephrology and Dialysis, San Giovanni Di Dio, Agrigento, Italy
| | - Alessandra Brocca
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Agrigento, Italy ; Department of IRRIV-International Renal Research Institute, Vicenza, Agrigento, Italy
| | - Massimo de Cal
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Agrigento, Italy ; Department of IRRIV-International Renal Research Institute, Vicenza, Agrigento, Italy
| | - Giorgio Vescovo
- Department of Internal Medicine, San Bortolo Hospital, Agrigento, Italy
| | - Antonio Granata
- Department of Nephrology and Dialysis, San Giovanni Di Dio, Agrigento, Italy
| | - Claudio Ronco
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Agrigento, Italy ; Department of IRRIV-International Renal Research Institute, Vicenza, Agrigento, Italy
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Hennessy EJ, Adam A, Aquila BM, Castriotta LM, Cook D, Hattersley M, Hird AW, Huntington C, Kamhi VM, Laing NM, Li D, MacIntyre T, Omer CA, Oza V, Patterson T, Repik G, Rooney MT, Saeh JC, Sha L, Vasbinder MM, Wang H, Whitston D. Discovery of a Novel Class of Dimeric Smac Mimetics as Potent IAP Antagonists Resulting in a Clinical Candidate for the Treatment of Cancer (AZD5582). J Med Chem 2013; 56:9897-919. [DOI: 10.1021/jm401075x] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Edward J. Hennessy
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Ammar Adam
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Brian M. Aquila
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Lillian M. Castriotta
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Donald Cook
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Maureen Hattersley
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Alexander W. Hird
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Christopher Huntington
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Victor M. Kamhi
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Naomi M. Laing
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Danyang Li
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Terry MacIntyre
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Charles A. Omer
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Vibha Oza
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Troy Patterson
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Galina Repik
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Michael T. Rooney
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Jamal C. Saeh
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Li Sha
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Melissa M. Vasbinder
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - Haiyun Wang
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
| | - David Whitston
- Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
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Long JS, Ryan KM. New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy. Oncogene 2012; 31:5045-60. [PMID: 22310284 DOI: 10.1038/onc.2012.7] [Citation(s) in RCA: 161] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 12/24/2011] [Accepted: 12/24/2011] [Indexed: 12/12/2022]
Abstract
Cancer is a multifaceted disease comprising a combination of genetic, metabolic and signalling aberrations, which severely disrupt the normal homeostasis of cell growth and death. Many oncogenic events while promoting tumour development also increase the sensitivity of cells to cell death stimuli including chemotherapeutic drugs. As a result, tumour cells often acquire the ability to evade death by inactivating cell death pathways that normally function to eliminate damaged and harmful cells. The impairment of cell death function is also often the reason for the development of chemotherapeutic resistance encountered during treatment. It is therefore necessary to achieve a comprehensive understanding of existing cell death pathways and the relevant regulatory components involved, with the intention of identifying new strategies to kill cancer cells. This review provides an insightful overview of the common forms of cell death signalling pathways, the interactions between these pathways and the ways in which these pathways are deregulated in cancer. We also discuss the emerging therapies targeted at activating or restoring cell death pathways to induce tumour cell death, which are currently being tested in clinical trials.
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Affiliation(s)
- J S Long
- Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Glasgow, UK
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Happi AN, Milner DA, Antia RE. Blood and Tissue Leukocyte Apoptosis inTrypanosoma bruceiInfected Rats. ACTA ACUST UNITED AC 2012. [DOI: 10.4303/jnp/n120101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Vařecha M, Potěšilová M, Matula P, Kozubek M. Endonuclease G interacts with histone H2B and DNA topoisomerase II alpha during apoptosis. Mol Cell Biochem 2011; 363:301-7. [PMID: 22160858 DOI: 10.1007/s11010-011-1182-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 11/24/2011] [Indexed: 11/25/2022]
Abstract
Apoptosis is a natural form of cell death involved in many physiological changes in the cell. Defects in the process of apoptosis can lead to serious diseases. During some apoptotic pathways, proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG) are released from the mitochondria and they translocate into the cell nuclei, where they probably participate in chromatin degradation together with other nuclear proteins. Exact mechanism of EndoG activity in cell nucleus is still unknown. Some interacting partners like flap endonuclease 1, DNase I, and exonuclease III were already suggested, but also other interacting partners were proposed. We conducted a living-cell confocal fluorescence microscopy followed by an image analysis of fluorescence resonance energy transfer to analyze the possibility of protein interactions of EndoG with histone H2B and human DNA topoisomerase II alpha (TOPO2a). Our results show that EndoG interacts with both these proteins during apoptotic cell death. Therefore, we can conclude that EndoG and TOPO2a may actively participate in apoptotic chromatin degradation. The possible existence of a degradation complex consisting of EndoG and TOPO2a and possibly other proteins like AIF and cyclophilin A have yet to be investigated.
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Affiliation(s)
- Miroslav Vařecha
- Centre for Biomedical Image Analysis, Faculty of Informatics, Masaryk University, Botanická 68a, 602 00 Brno, Czech Republic.
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30
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Synthesis and NMR elucidation of novel tetrapeptides. J Pept Sci 2011; 18:114-21. [DOI: 10.1002/psc.1423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Revised: 08/31/2011] [Accepted: 09/09/2011] [Indexed: 11/07/2022]
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GAO CHUN, GUO WENJUAN, WANG AIYING. Significance of decreased apoptosis, role of Bid expression and Bcl-Xl/Bid ratio in human jejunal stromal tumors. APMIS 2011; 120:171-81. [DOI: 10.1111/j.1600-0463.2011.02822.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Quaresma JAS, Lima LWDO, Fuzii HT, Libonati RMF, Pagliari C, Duarte MIS. Immunohistochemical evaluation of macrophage activity and its relationship with apoptotic cell death in the polar forms of leprosy. Microb Pathog 2010; 49:135-40. [PMID: 20510345 DOI: 10.1016/j.micpath.2010.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2009] [Revised: 05/02/2010] [Accepted: 05/04/2010] [Indexed: 11/19/2022]
Abstract
The objective of the present study was to investigate the correlation between macrophage activity and apoptosis in the polar forms of leprosy because the immunopathological phenomena involved in these forms are still poorly understood. For this purpose, 29 skin biopsy samples obtained from patients with the polar forms of leprosy were analyzed. Macrophage activity and apoptosis were evaluated by immunohistochemistry using lysozyme, CD68, iNOS and caspase 3 as markers. The nonparametric Mann-Whitney test and Spearman's linear correlation test were used for statistical analysis. The results suggest that the apoptosis rate is under the direct influence of macrophage activity in lesions of patients with the tuberculoid form. In contrast, in lepromatous lesions other factors seem to induce programmed cell death, possibly TGF-beta. Further studies are necessary to identify additional factors involved in the immunopathogenesis of leprosy.
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Jiang CG, Li JB, Xu HM, Yu M, Wu T, Liu FR. Effect of cimetidine on the proliferation and apoptosis of human gastric cancer cell line SGC-7901. Shijie Huaren Xiaohua Zazhi 2007; 15:118-122. [DOI: 10.11569/wcjd.v15.i2.118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of cimetidine on the proliferation and apoptosis of human gastric cancer cell line SGC-7901 and its related mechanism.
METHODS: Human gastric cancer cell SGC-7901 was cultivated by routine method, then treated with different concentrations of cimetidine. The proliferation of SGC-7901 cells was examined by MTT assay, and the cell cycle and apoptosis were detected by flow cytometry. After Hoechst33258 staining, the morphologic changes of SGC-7901 cells were observed under fluorescence microscope, and the ultrastructure of the cells was investigated by transmission electron microscopy. The levels of Bcl-2 and Bax protein expression were detected by Western blot analysis.
RESULTS: After dealing with cimetidine (0.5, 1, 2.5, 5, 10 mmol/L) for 24 and 48 hours, we found that cimetidine significantly inhibited the proliferation of SGC-7901 cells in a time- and concentration-dependent manner (24 h: 0.705 ± 0.018, 0.560 ± 0.038, 0.408 ± 0.029, 0.276 ± 0.042, 0.205 ± 0.031 vs 0.803 ± 0.012, P < 0.05; 48 h: 0.902 ± 0.024, 0.671 ± 0.015, 0.420 ± 0.030, 0.180 ± 0.037, 0.117 ± 0.021 vs 1.079 ± 0.040, P < 0.05), whereas there was no significant cytotoxic effect as the concentration was below 0.25 mmol/L. cimetidine at the concentrations of 0.5, 1, 2.5, 5, and 10 mmol/L induced typical apoptosis of SGC-7901 cells, and flow cytometry showed an apoptosis peak. The percentage of G0/G1-phase cells was significantly increased (60.83% ± 2.27%, 67.21% ± 1.18%, 75.15% ± 4.01%, 81.88% ± 3.10%, 86.99% ± 1.43% vs 50.28% ± 1.97%, P < 0.05). The expression of Bcl-2 protein was decreased while that of Bax protein was increased following cimetidine treatment.
CONCLUSION: Cimetidine may inhibit the proliferation of SGC-7901 cells through inducing cell apoptosis and cell cycle arrest.
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Adişen E, Gülekon A, Erdem O, Dursun A, Gürer MA. The effects of calcipotriol and methylprednisolone aseponate on bcl-2, p53 and ki-67 expression in psoriasis. J Eur Acad Dermatol Venereol 2006; 20:527-33. [PMID: 16684279 DOI: 10.1111/j.1468-3083.2006.01508.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE The decrease of physiological apoptosis in the psoriatic lesions is thought to be involved in the pathogenesis of psoriasis, and induction of apoptosis was shown to contribute to the regression of psoriatic hyperplasia. In the present study, we compared the effects of calcipotriol and methylprednisolone aseponate (MPA) treatments on bcl-2, p53 and ki-67 expressions in psoriatic patients in order to define a relationship between regulation of apoptosis and healing process in psoriasis. METHODS Thirty psoriatic patients with stable and moderate chronic plaque psoriasis applied either calcipotriol or MPA ointment for 6 weeks twice daily. Evaluation of bcl-2, p53 and ki-67 positivity was performed at baseline and was repeated at sixth week for each therapy. RESULTS The mean percentage of positive keratinocytes was 8.63 +/- 7.15% for p53, 20.66 +/- 14.45% for ki-67, and 3.74 +/- 2.83% for bcl-2 in psoriatic skin at baseline. Normal skin values were 3.27 +/- 3.21% for p53, 4.93 +/- 4.77% for ki-67, and 1.80 +/- 0.41% for bcl-2. The psoriatic skin showed higher ki-67 (P < 0.05) and bcl-2 (P < 0.05) expression rates when compared to normal skin. The p53 positivity observed in psoriatic skin and normal skin was not significantly different (P > 0.05). Following calcipotriol and MPA treatments, there was a significant reduction in p53 and ki-67 positivity accompanied by an increase in bcl-2 positivity (P < 0.05 each). No significant differences were found at sixth week between calcipotriol and MPA groups with respect to p53, ki-67 and bcl-2 positivity (P > 0.05). The post-treatment psoriatic skin showed lower expression of p53, higher expressions of ki-67 and bcl-2 when compared to normal skin (P < 0.05 each). CONCLUSION The results of this study provide evidence that both calcipotriol and MPA decrease the p53 and ki-67 expression and increase bcl-2 expression. However, it should further be elucidated if these changes were the common behaviour of psoriatic keratinocytes to any antipsoriatic medication.
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Affiliation(s)
- E Adişen
- Department of Dermatology, Gazi University Faculty of Medicine, Ankara, Turkey
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35
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Chechina OY, Zhoukova OB, Ryazantseva NV, Novitsky VV, Nasyrova RF, Mikheyev SL, Litvak MM. Virus-induced modulation of apoptotic cell death program. BULLETIN OF SIBERIAN MEDICINE 2005. [DOI: 10.20538/1682-0363-2005-4-78-83] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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O'Sullivan S, Cormican L, Burke CM, Poulter LW. Fluticasone induces T cell apoptosis in the bronchial wall of mild to moderate asthmatics. Thorax 2004; 59:657-61. [PMID: 15282384 PMCID: PMC1747107 DOI: 10.1136/thx.2002.001586] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Cytokines which signal via the gamma chain of the interleukin (IL)-2 receptor and the interferons (IFNs) have been shown to enhance T cell survival in vitro by rescuing cells from apoptosis. METHODS A study was undertaken to determine whether treatment with inhaled fluticasone propionate (FP; 250 microg twice daily) for 2 weeks could modulate production of IL-15 or IFN-beta and thereby affect T cell survival in bronchial tissue of 10 patients with mild/moderate asthma. Bronchial biopsy specimens were taken before and on completion of treatment. RESULTS The mean (95% CI) number of T cells per unit area decreased in the asthmatic group following 2 weeks of treatment with FP (from 7.0 (5.6 to 8.4) to 4.5 (4.0 to 5.1); p = 0.001). There was an increase in the percentage of T cells undergoing apoptosis following FP treatment as assessed by T cell/TUNEL staining (from 4.5 (2.6 to 6.4) to 8.7 (6.6 to 10.8); p = 0.0001). The percentage of cells staining for IL-15 and IFN-beta in the lamina propria, determined by an alkaline phosphatase biotin streptavidin technique, decreased significantly from baseline values of 31.6 (23.4 to 39.7) to 19.6 (12.5 to 26.7), p = 0.039 for IL-15 and from 18.9 (13.5 to 24.4) to 9.5 (5.9 to 13.1), p = 0.007 for IFN-beta following 2 weeks of treatment with FP. However, only the decrease in the percentage of cells staining for IL-15 was significantly correlated with an increased number of apoptotic T cells following treatment (p = 0.008). CONCLUSION These findings support a novel mechanism for the ability of inhaled corticosteroids to decrease T cell numbers, possibly by downregulation of the cytokine IL-15.
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Affiliation(s)
- S O'Sullivan
- Department of Immunology, Royal Free and University College Hospital Medical School, London NW3 2QG, UK.
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Tang Z, Tang Y, Fu L. Growth inhibition and apoptosis induction in human hepatoma cells by tanshinone II A. JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY. MEDICAL SCIENCES = HUA ZHONG KE JI DA XUE XUE BAO. YI XUE YING DE WEN BAN = HUAZHONG KEJI DAXUE XUEBAO. YIXUE YINGDEWEN BAN 2004; 23:166-8, 172. [PMID: 12973939 DOI: 10.1007/bf02859946] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
In order to study the effect of tanshinone II A on growth and apoptosis in human hepatoma cell line BEL-7402 in vitro, the human hepatoma cell line BEL-7402 was treated with tanshinone II A at various concentrations for 72 h. Growth suppression was evaluated by MTT assay; apoptosis-related alterations in morphology and biochemistry were ascertained under cytochemical staining (Hoechst 33258), transmission electron microscopy (TEM), and DNA agarose gel electrophoresis. Apoptotic rate was quantified by flow cytometry (FCM). The results showed that Tanshinone II A could inhibit the growth of hepatoma cells in a dose-dependent manner, with IC50 value being 6.28 micrograms/ml. After treatment with 1-10 micrograms/ml tanshinone II A for 72 h, BEL-7402 cells apoptosis with nuclear chromatin condensation and fragmentation as well as cell shrinkage and the formation of apoptotic bodies were observed. DNA ladder could be demonstrated on DNA electrophoresis. FCM analysis showed hypodiploid peaks on histogram, and the apoptotic rates at 5 micrograms/ml concentration for 12 h, 24 h, 36 h, 48 h and 72 h were (2.32 +/- 0.16)%, (3.01 +/- 0.35)%, (3.87 +/- 0.43)%, (6.73 +/- 0.58)% and (20.85 +/- 1.74)% respectively, which were all significantly higher than those in the control group (1.07 +/- 0.13)%. It is concluded that Tanshinone II A could induce human hepatoma cell line BEL-7402 apoptosis, which may be related to the mechanism of growth inhibition.
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Affiliation(s)
- Zhongzhi Tang
- Wuhan General Hospital, Guangzhou Command of PLA, Wuhan 430070
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38
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Lesur O, Brisebois M, Thibodeau A, Chagnon F, Lane D, Füllöp T. Role of IFN-gamma and IL-2 in rat lung epithelial cell migration and apoptosis after oxidant injury. Am J Physiol Lung Cell Mol Physiol 2004; 286:L4-L14. [PMID: 12922984 DOI: 10.1152/ajplung.00367.2002] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In the present study, IFN-gamma exposure to primary cultures of rat type II epithelial cells (TIIP) upregulated membrane expression of the common gamma-chain of the IL-2 receptor (approximately 2.5- to 4-fold increase) and redistributed receptor affinity in TIIP, as assessed by Western blot, cell, and tissue histochemistry and Scatchard analysis. As for restitution processes of the lung epithelium, functionality of IL-2R on TIIP was conditional to IFN-gamma exposure: 1) IFN-gamma priming promoted a fivefold increase of IL-2-driven TIIP locomotion (P < 0.05 vs. control at 100 U/ml) and 2) IFN-gamma coincubation with IL-2 reduced bleomycin-induced TIIP apoptosis in vitro by 25% (caspase-3 activity) and by approximately 70% (TdT-mediated dUTP nick end labeling/4',6'-diamidino-2-phenylindole assay) as well as in vivo by approximately 90% (caspase-3 activity; P < 0.05 vs. control). Sustained p42/44 extracellular signal-regulated kinase activity played a protective role in this process, whereas specific inhibition by PD-98059 (50 microM) significantly reversed bleomycin-induced TIIP apoptosis (P < 0.05 vs. control). From these in vitro and in vivo data, it is proposed that combinations of IFN-gamma and IL-2 can drive repair activity of TIIP by stimulating migration and preventing programmed cell death, both of which are speculated to be very fast restitution events after oxidant-induced acute lung injury.
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Affiliation(s)
- Olivier Lesur
- Groupe de Recherche en Physiopathologie Respiratoire, and Soins Intensif Médicaux, Université de Sherbrooke, Québec, Canada, J1H 5N4.
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Junker K, Müller KM, Bosse U, Klinke F, Heinecke A, Thomas M. [Apoptosis and tumor regression in locally advanced non-small cell lung cancer with neoadjuvant therapy]. DER PATHOLOGE 2003; 24:214-9. [PMID: 12739056 DOI: 10.1007/s00292-002-0607-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Dysregulation of apoptosis is closely associated with malignant cell transformation. On the other hand, apoptosis is induced by chemotherapy or irradiation. Therefore, in 54 patients with locally advanced non-small cell lung cancer (NSCLC, 36 squamous cell carcinomas, 18 adenocarcinomas, stage IIIA/IIIB), apoptotic indices were comparatively analysed before onset and after termination of neoadjuvant therapy. The results were compared with the response to neoadjuvant therapy (extent of therapy-induced tumour regression) as well as the survival times. A statistically significant difference could not be established between pre-therapeutically and post-surgically established apoptotic indices (mean values: 0.93% vs. 1.1%). Neither before therapy nor after surgery did the apoptotic indices show a significant predictive value concerning different overall survival times. These results suggest that neoadjuvant therapy does not modify the extent of apoptosis in lung cancer in the long term. Only a few weeks after the completion of the neoadjuvant chemoradiotherapy this contributes to a net proliferation of the residual tumour tissue which is largely equivalent to that of the untreated tumour.
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Affiliation(s)
- K Junker
- Institut für Pathologie, Universitätsklinik Bergmannsheil, Bochum.
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40
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Agust AGN, Gari PG, Sauleda J, Busquets X. Weight loss in chronic obstructive pulmonary disease. Mechanisms and implications. Pulm Pharmacol Ther 2003; 15:425-32. [PMID: 12406664 DOI: 10.1006/pupt.2002.0385] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Weight loss occurs frequently in patients with chronic obstructive pulmonary disease (COPD). Although the precise cellular mechanisms underlying weight loss in COPD are unclear, this is a clinically relevant phenomenon because it contributes to limit the exercise capacity of these patients and, therefore, it jeopardizes their quality of life. More importantly, it is a negative prognostic factor that is independent of the degree of lung function impairment present. Thus, weight loss in COPD constitutes a new therapeutic target. This article reviews the mechanisms and potential consequences of weight loss in COPD and highlights areas that needed future research. It is hoped that a better understanding of its pathogenesis may eventually contribute to the development of new therapeutic strategies that contribute to improve the well-being and/or long-term prognosis of patients suffering from this devastating disease and, potentially, from others characterized also by unexplained weight loss.
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Affiliation(s)
- Alvar G N Agust
- Servei de Pneumologia, Hospital Universitari Son Dureta, Palma de Mallorca, Spain.
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41
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Xu AG, Li SG, Liu JH, Gan AH. Function of apoptosis and expression of the proteins Bcl-2, p53 and C-myc in the development of gastric cancer. World J Gastroenterol 2001; 7:403-6. [PMID: 11819799 PMCID: PMC4688731 DOI: 10.3748/wjg.v7.i3.403] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- A G Xu
- Research Laboratory of Digestive Disease, Huizhou Central People's Hospital, No.41 Elingbei Road, Huizhou 516001, Guangdong Province, China
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42
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Agustí A, Sauleda J, Morlá M, Miralles C, Busquets X. [Skeletal muscle dysfunction in COPD. Cell mechanisms. A.G.N]. Arch Bronconeumol 2001; 37:197-205. [PMID: 11412505 DOI: 10.1016/s0300-2896(01)75049-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- A Agustí
- Servicio de Neumología. Hospital Universitari Son Dureta. Palma de Mallorca.
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43
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Pneumoconiosis in Coal Workers: Cellular Concepts of Dust-Induced Lung Injury, Radiographic Diagnosis, and Pulmonary Infections With Mycobacteria. ACTA ACUST UNITED AC 2001. [DOI: 10.1097/00045413-200101000-00003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Abstract
The balance between cell survival and death is under tight genetic control. A multiplicity of extracellular signals and intracellular mediators is involved in maintaining this balance. When the cell is exposed to physical, biochemical or biological injury, or deprived of necessary substances, it activates a series of stress-response genes. With minimal insults, the cell may recover. With greater insults, single cell death, or apoptosis, results; the cell dies and is recycled to its neighbours. If the insult overwhelms a large number of cells then necrosis ensues, with an accompanying inflammatory response. Dysregulation of the controlling mechanisms of this system results in disease. Deficient apoptosis is associated with cancer, auto-immunity and viral infections. Excessive apoptosis is associated with ischaemic heart disease, stroke, neurodegenerative disease, sepsis and multiple organ dysfunction syndrome. There are myriad therapeutic options unfolding as understanding is gained of apoptosis and its control.
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Affiliation(s)
- P C Kam
- Department of Anaesthesia and Pain Management, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
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45
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Sun Y, Clinkenbeard KD, Ownby CL, Cudd L, Clarke CR, Highlander SK. Ultrastructural characterization of apoptosis in bovine lymphocytes exposed to Pasteurella haemolytica leukotoxin. Am J Vet Res 2000; 61:51-6. [PMID: 10630778 DOI: 10.2460/ajvr.2000.61.51] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To characterize ultrastructural changes of bovine lymphocytes exposed to Pasteurella haemolytica leukotoxin (LKT). SAMPLE POPULATION Partially purified LKT from a wild type P. haemolytica A1 strain and inactive pro-LKT from an isogeneic mutant Phaemolytica strain. Isolated bovine lymphocytes were obtained from 2 healthy calves. PROCEDURE Isolated bovine lymphocytes were incubated with various concentrations of LKT and pro-LKT for 3 hours at 37 C and examined by use of transmission electron microscopy. A cytochemical Klenow DNA fragmentation assay was used to examine lymphocytes for DNA fragmentation. RESULTS Lymphocytes incubated with LKT at a high concentration (1.0 toxic U/ml) had ultrastructural evidence of cytoplasmic and nuclear membrane rupture and swelling or lysis of mitochondria. Low concentrations of leukotoxin (0.1 toxic U/ml) induced DNA fragmentation in 80% of lymphocytes. Ultrastructurally, these cells had nuclear membrane blebbing, cytoplasmic vaculation, chromatin condensation, nuclear fragmentation, and membrane-bound apoptotic bodies. Incubation of lymphocytes with LKT at extremely low concentrations (0.001 toxic U/ml) or with pro-LKT did not alter their ultrastructure. Inclusion of 0.5 mM ZnCl2 in the medium blocked leukotoxin-induced ultrastructural changes in bovine lymphocytes. CONCLUSIONS AND CLINICAL RELEVANCE Low concentrations of LKT induce apoptosis and high concentrations induce oncotic cell lysis in bovine lymphocytes. The ability of low LKT concentrations to induce apoptosis in host leukocytes may allow bacteria to escape host immune surveillance and colonize the host.
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Affiliation(s)
- Y Sun
- Department of Anatomy, Pathology and Pharmacology, College of Veterinary Medicine, Oklahoma State University, Stillwater 74078, USA
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46
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Tao K, Chen D, Tian Y, Lu X, Yang X. The relationship between apoptosis and the expression of proliferating cell nuclear antigen and the clinical stages in gastric carcinoma. Curr Med Sci 2000; 20:222-4. [PMID: 11215055 DOI: 10.1007/bf02886997] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2000] [Indexed: 12/20/2022]
Abstract
The relationship between the apoptosis and the expression of proliferating cell nuclear antigen (PCNA) and the clinical stages in gastric cancers was studied. By using terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) technique and PCNA immunohistochemical staining, the apoptosis and the expression of PCNA in tissue of gastric carcinoma were assayed in situ, the index of apoptosis (AI), index of PCNA (PI) and the rate of AI/PI were calculated. AI and PI in gastric cancer tissues were (6.5 +/- 3.7)% and (49.8 +/- 15.9)% respectively, and the rate of AI/PI was 0.13 +/- 0.05, which were obviously different from those of normal gastric mucosa in paragastric cancer (P < 0.01). With the advanced TNM stages of gastric carcinoma, the AI was decreased, PI was increased and the rate of AI/PI decreased in gastric carcinoma. There was significant difference in them between the gastric cancer tissues and normal gastric mucosa in pericarcinoma in TNM stage II to IV (P < 0.05). It was suggested that the decreased apoptotic cells and the increased proliferating cells were obviously related to the tumor genesis and tumor progression in gastric carcinoma. The AI, PI and the rate of AI/PI would become the prognostic factors in advanced gastric carcinoma.
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Affiliation(s)
- K Tao
- Department of Surgery, Xiehe Hospital, Tongji Medical University, Wuhan 430030
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47
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Pläsier B, Lloyd DR, Paul GC, Thomas CR, Al-Rubeai M. Automatic image analysis for quantification of apoptosis in animal cell culture by annexin-V affinity assay. J Immunol Methods 1999; 229:81-95. [PMID: 10556693 DOI: 10.1016/s0022-1759(99)00107-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Apoptosis is a form of cell death in which the dying cell plays an active part in its demise. At the morphological level, it is characterised by cell shrinkage rather than the swelling seen in necrotic cell death. In cell culture, apoptosis limits the yield of economically and medically important products, and can result in synthesis of imperfect molecules. Therefore, this process must be identified, monitored and fully understood, so that a means to regulate it can be developed. We have developed a new automatic image analysis assay for detecting apoptosis in animal cell culture on the basis of the annexin-V affinity assay. The results of this assay were compared with data generated by flow cytometry and manual scoring. All three methods were found to correspond well but image analysis like flow cytometry offers operator-independent results, and can be used as a tool for rapid monitoring of viable cell number, apoptosis and necrosis in animal cell culture. Furthermore, reduction in cell size was measured and was found to precede the appearance of phosphatidylserine on the cell surface.
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Affiliation(s)
- B Pläsier
- SERC Centre for Bioprocess Engineering, School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham, UK
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48
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Gupta A, Sharma VK, Vohra H, Ganguly NK. Spontaneous apoptosis in peripheral blood mononuclear cells of leprosy patients: role of cytokines. FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY 1999; 24:49-55. [PMID: 10340712 DOI: 10.1111/j.1574-695x.1999.tb01264.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Peripheral blood mononuclear cells from leprosy patients underwent spontaneous apoptosis upon culture for 24 h. The apoptosis was inhibited by anti-TNFalpha antibodies and to a certain extent by anti-IL-1alpha and IL-6, thus showing that T(H)2-type cytokines (mainly TNFalpha) are responsible for inducing apoptosis. This cytokine-mediated apoptosis could be inhibited by ionomycin and zinc, thereby suggesting that these metal ions can be used to decrease the levels of these inflammatory cytokines in various diseases.
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Affiliation(s)
- A Gupta
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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49
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Ruppová K, Urbancíková M, Wsólová L, Slamenová D. Apoptosis Versus Cytotoxicity in HeLa Cells Exposed to Paracetamol. Altern Lab Anim 1999; 27:403-12. [PMID: 25470679 DOI: 10.1177/026119299902700316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Apoptosis is a programmed form of cell death which occurs in response to specific stimuli. It is distinguished from necrotic or accidental cell death by unique events, including the degradation of chromatin and a loss of cellular volume. In contrast to necrotic cell death, cell membrane integrity and mitochondrial function are thought to be maintained until the apoptotic process is well advanced. One of the novel assays for detecting apoptosis is flow cytometry. In our experiments, we used a flow cytometric assay to detect DNA changes in a human cell line (HeLa) exposed to paracetamol, by measuring propidium iodide binding. We were able to detect the apoptotic process in cells exposed to paracetamol. Apoptosis did not correlate with cytotoxicity, and was only found in samples exposed to 4-5mg/ml paracetamol for 8 hours in minimum essential medium and incubated in fresh medium without paracetamol for 14-19 hours. The greatest effect was noted 18 hours after paracetamol exposure. These results were confirmed by studying cell morphology and chromatin condensation by fluorescent microscopy with the fluorochromes acridine orange and ethidium bromide. Our results support the hypothesis that, in cultured cells, apoptosis is induced by a relatively narrow range of chemical concentrations which are known to inhibit the cell cycle, and that apoptosis and inhibition of cell proliferation coincide to some degree.
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Affiliation(s)
- K Ruppová
- Institute of Preventive and Clinical Medicine, Limbová 14, 833 01 Bratislava, Slovakia
| | - M Urbancíková
- Institute of Preventive and Clinical Medicine, Limbová 14, 833 01 Bratislava, Slovakia
| | - L Wsólová
- Institute of Preventive and Clinical Medicine, Limbová 14, 833 01 Bratislava, Slovakia
| | - D Slamenová
- Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 01 Bratislava, Slovakia
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50
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Sun Y, Clinkenbeard KD, Clarke C, Cudd L, Highlander SK, Dabo SM. Pasteurella haemolytica leukotoxin induced apoptosis of bovine lymphocytes involves DNA fragmentation. Vet Microbiol 1999; 65:153-66. [PMID: 10078599 DOI: 10.1016/s0378-1135(98)00286-7] [Citation(s) in RCA: 90] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
It has been reported that Pasteurella haemolytica leukotoxin (LKT) induces morphologic changes in bovine leukocytes consistent with apoptosis in vitro, but DNA fragmentation was not observed. We investigated whether bovine lymphocytes undergo DNA fragmentation during LKT-induced apoptosis. Bovine peripheral blood lymphocytes were isolated by density gradient centrifugation and exposed to LKT or inactive pro-LKT protein from a lktC- mutant strain. After exposure, DNA fragmentation in lymphocytes was quantified colorimetrically by diphenylamine assay and visualized by agarose gel electrophoresis. At high LKT concentrations, bovine lymphocytes were lysed, but at low concentrations, LKT caused DNA fragmentation characteristic of apoptosis. Maximal DNA fragmentation in bovine lymphocytes was induced by 0.1 TU ml(-1) LKT following 3 h exposure, but only background level of DNA fragmentation was observed with the inactive pro-LKT. Equine lymphocytes that are resistant to LKT intoxication did not show DNA fragmentation following exposure to LKT. Preincubation of LKT with a neutralizing anti-LKT monoclonal antibody inhibited LKT-induced DNA fragmentation. Electrophoresis of DNA from bovine lymphocytes treated with 0.1 TU ml(-1) LKT demonstrated the typical 'ladder' pattern of internucleosomal DNA cleavage, the hallmark of apoptosis associated with activation of endonucleases. LKT-induced DNA fragmentation was inhibited by 0.5 mM ZnCl2, an endonuclease inhibitor. The results indicated that LKT at low concentrations induced apoptotic cell death of bovine lymphocytes, which may play a role in initiation and persistence of P. haemolytica infection.
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Affiliation(s)
- Y Sun
- Department of Anatomy, Pathology and Pharmacology, College of Veterinary Medicine, Oklahoma State University, Stillwater 74078, USA.
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