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Li Y, Xu H, Ma Z, Li Q, Xiong Y, Xiong X, Li J, Lan D, Fu W. Comprehensive cognition of yak ( Bos grunniens) AIFM2 gene and its anti-ferroptosis role in bisphenol A-induced fetal fibroblast model. Anim Biotechnol 2024; 35:2377209. [PMID: 39037081 DOI: 10.1080/10495398.2024.2377209] [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] [Indexed: 07/23/2024]
Abstract
Apoptosis-inducing factor mitochondrion-associated 2 (AIFM2) has been identified as a gene with anti-ferroptosis properties. To explore whether AIFM2 exerts anti-ferroptosis role in yaks (Bos grunniens), we cloned yak AIFM2 gene and analyzed its biological characteristics. The coding region of AIFM2 had 1122 bp and encoded 373 amino acids, which was conserved in mammals. Next, RT-qPCR results showed an extensive expression of AIMF2 in yak tissues. Furthermore, we isolated yak skin fibroblasts (YSFs) and established a bisphenol A (BPA)-induced ferroptosis model to further investigate the role of AIFM2. BPA elevated oxidative stress (reactive oxygen species, ROS) and lipid peroxidation (malondialdehyde, MDA and BODIPY), and reduced cell viability and antioxidant capacity (glutathione, GSH), with the severity depending on the dosage. Of note, a supplement of Ferrostatin-1 (Fer), an inhibitor of ferroptosis, restored the previously mentioned indicators. Subsequently, we constructed an AIFM2 overexpression vector and designed AIFM2 specific interfering siRNAs, which were transfected into YSFs. The results showed that overexpressing AIFM2 alleviated ferroptosis, characterizing by significant changes of cell viability, ROS, BODIPY, MDA and GSH. Meanwhile, interfering AIFM2 aggravated ferroptosis, demonstrating the critical anti-ferroptosis role of the yak AIFM2 gene. This study shed light on further exploring the molecular mechanism of AIFM2 in plateau adaptability.
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Affiliation(s)
- Yueyue Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Hongmei Xu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Zifeng Ma
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Qiao Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
| | - Yan Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
- Key Laboratory of Animal Science of National Ethnic Affairs Commission of China, Southwest Minzu University, Chengdu, China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Xianrong Xiong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
- Key Laboratory of Animal Science of National Ethnic Affairs Commission of China, Southwest Minzu University, Chengdu, China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Jian Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
- Key Laboratory of Animal Science of National Ethnic Affairs Commission of China, Southwest Minzu University, Chengdu, China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Daoliang Lan
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
- Key Laboratory of Animal Science of National Ethnic Affairs Commission of China, Southwest Minzu University, Chengdu, China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
| | - Wei Fu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, Southwest Minzu University, Chengdu, China
- Key Laboratory of Animal Science of National Ethnic Affairs Commission of China, Southwest Minzu University, Chengdu, China
- Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, China
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Antonioli L, Fornai M, Pellegrini C, Pacher P, Haskó G. Adenosine signaling as target in cardiovascular pharmacology. Curr Opin Pharmacol 2023; 71:102393. [PMID: 37450948 PMCID: PMC10527223 DOI: 10.1016/j.coph.2023.102393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 06/14/2023] [Indexed: 07/18/2023]
Abstract
Increasing evidence demonstrated the relevance of adenosine system in the onset and development of cardiovascular diseases, such as hypertension, myocardial infarct, ischemia, hypertension, heart failure, and atherosclerosis. In this regard, intense research efforts are being focused on the characterization of the pathophysiological significance of adenosine, acting at its membrane receptors named A1, A2A, A2B, and A3 receptors, in cardiovascular diseases. The present review article provides an integrated and comprehensive overview about current clinical and pre-clinical evidence about the role of adenosine in the pathophysiology of cardiovascular diseases. Particular attention has been focused on current scientific evidence about the pharmacological ligands acting on adenosine pathway as useful tools to manage cardiovascular diseases.
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Affiliation(s)
- Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, 56126, Pisa, Italy
| | - Matteo Fornai
- The Institution is Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Carolina Pellegrini
- The Institution is Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Pál Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, 20892, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, 10032, USA.
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Diab T, Mohamed TM, Hamed A, Gaber M. Induction of Apoptosis by Nano-Synthesized Complexes of H2L and its Cu(II) Complex in Human Hepatocellular Carcinoma Cells. Anticancer Agents Med Chem 2021; 21:1151-1159. [PMID: 32013853 DOI: 10.2174/1871520620666200204103756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 12/18/2019] [Accepted: 12/25/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Chemotherapy is currently the most utilized treatment for cancer. Therapeutic potential of metal complexes in cancer therapy has attracted a lot of interest. The mechanisms of action of most organometallic complexes are poorly understood. OBJECTIVE This study was designed to explore the mechanisms governing the anti-proliferative effect of the free ligand N1,N6-bis((2-hydroxynaphthalin-1-yl)methinyl)) adipohydrazone (H2L) and its complexes of Mn(II), Co(II), Ni(II) and Cu(II). METHODS Cells were exposed to H2L or its metal complexes where cell viability determined by MTT assay. Cell cycle was analysed by flow cytometry. In addition, qRT-PCR was used to monitor the expression of Bax and Bcl-2. Moreover, molecular docking was carried out to find the potentiality of Cu(II) complex as an inhibitor of Adenosine Deaminase (ADA). ADA, Superoxide Dismutase (SOD) and reduced Glutathione (GSH) levels were measured in the most affected cancer cell line. RESULTS The obtained results demonstrated that H2L and its Cu(II) complex exhibited a strong cytotoxic activity compared to other complexes against HepG2 cells (IC50=4.14±0.036μM/ml and 3.2±0.02μM/ml), respectively. Both H2L and its Cu(II) complex induced G2/M phase cell cycle arrest in HepG2 cells. Additionally, they induced apoptosis in HepG2 cells via upregulation of Bax and downregulation of Bcl-2. Interestingly, the activity of ADA was decreased by 2.8 fold in HepG2 cells treated with Cu(II) complex compared to untreated cells. An increase of SOD activity and GSH level in HepG2 cells compared to control was observed. CONCLUSION The results concluded that Cu(II) complex of H2L induced apoptosis in HepG2 cells. Further studies are needed to confirm its anti-cancer effect in vivo.
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Affiliation(s)
- Thoria Diab
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Tarek M Mohamed
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Alaa Hamed
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt
| | - Mohamed Gaber
- Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Egypt
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Antonioli L, Fornai M, Pellegrini C, D'Antongiovanni V, Turiello R, Morello S, Haskó G, Blandizzi C. Adenosine Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1270:145-167. [PMID: 33123998 DOI: 10.1007/978-3-030-47189-7_9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Adenosine, deriving from ATP released by dying cancer cells and then degradated in the tumor environment by CD39/CD73 enzyme axis, is linked to the generation of an immunosuppressed niche favoring the onset of neoplasia. Signals delivered by extracellular adenosine are detected and transduced by G-protein-coupled cell surface receptors, classified into four subtypes: A1, A2A, A2B, and A3. A critical role of this nucleoside is emerging in the modulation of several immune and nonimmune cells defining the tumor microenvironment, providing novel insights about the development of novel therapeutic strategies aimed at undermining the immune-privileged sites where cancer cells grow and proliferate.
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Affiliation(s)
- Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | - Roberta Turiello
- Department of Pharmacy, University of Salerno, Fisciano, Italy.,PhD Program in Drug discovery and Development, Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - Silvana Morello
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Nakajima Y, Kuribayashi K, Ishigaki H, Tada A, Negi Y, Minami T, Takahashi R, Doi H, Kitajima K, Yokoi T, Kijima T. Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma. Cancer Invest 2020; 38:356-364. [PMID: 32468861 DOI: 10.1080/07357907.2020.1776313] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 10/24/2022]
Abstract
Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.
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MESH Headings
- Adenosine Deaminase/genetics
- Adult
- Aged
- Aged, 80 and over
- Female
- Humans
- Lung Neoplasms/diagnosis
- Lung Neoplasms/diagnostic imaging
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Male
- Mesothelioma/diagnosis
- Mesothelioma/diagnostic imaging
- Mesothelioma/genetics
- Mesothelioma/pathology
- Mesothelioma, Malignant
- Middle Aged
- Mycobacterium tuberculosis/isolation & purification
- Mycobacterium tuberculosis/pathogenicity
- Neoplasms/diagnosis
- Neoplasms/diagnostic imaging
- Neoplasms/genetics
- Neoplasms/pathology
- Pleural Effusion, Malignant/diagnosis
- Pleural Effusion, Malignant/diagnostic imaging
- Pleural Effusion, Malignant/genetics
- Pleural Effusion, Malignant/pathology
- Pleural Neoplasms/diagnosis
- Pleural Neoplasms/diagnostic imaging
- Pleural Neoplasms/genetics
- Pleural Neoplasms/pathology
- Thoracoscopy
- Tuberculosis, Pleural/diagnosis
- Tuberculosis, Pleural/genetics
- Tuberculosis, Pleural/microbiology
- Tuberculosis, Pleural/pathology
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Affiliation(s)
- Yasuhiro Nakajima
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kozo Kuribayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Department of Thoracic Oncology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirotoshi Ishigaki
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Akio Tada
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoshiki Negi
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshiyuki Minami
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ryo Takahashi
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hiroshi Doi
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kazuhiro Kitajima
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takashi Yokoi
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Department of Thoracic Oncology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takashi Kijima
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
- Department of Thoracic Oncology, Hyogo College of Medicine, Nishinomiya, Japan
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Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway. Int J Mol Sci 2020; 21:ijms21030814. [PMID: 32012688 PMCID: PMC7037771 DOI: 10.3390/ijms21030814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 01/22/2020] [Accepted: 01/25/2020] [Indexed: 12/17/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a lethal disease with increasing incidence worldwide. Previous study showed that CCA was sensitive to adenosine. Thereby, molecular mechanisms of CCA inhibition by adenosine were examined in this study. Our results showed that adenosine inhibited CCA cells via an uptake of adenosine through equilibrative nucleoside transporters (ENTs), instead of activation of adenosine receptors. The inhibition of ENTs by NBTI caused the inhibitory effect of adenosine to subside, while adenosine receptor antagonists, caffeine and CGS-15943, failed to do so. Intracellular adenosine level was increased after adenosine treatment. Also, a conversion of adenosine to AMP by adenosine kinase is required in this inhibition. On the other hand, inosine, which is a metabolic product of adenosine has very little inhibitory effect on CCA cells. This indicates that a conversion of adenosine to inosine may reduce adenosine inhibitory effect. Furthermore, there was no specific correlation between level of proinflammatory proteins and CCA responses to adenosine. A metabolic stable analog of adenosine, 2Cl-adenosine, exerted higher inhibition on CCA cell growth. The disturbance in intracellular AMP level also led to an activation of 5′ AMP-activated protein kinase (AMPK). Accordingly, we proposed a novel adenosine-mediated cancer cell growth and invasion suppression via a receptor-independent mechanism in CCA.
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Camici M, Garcia-Gil M, Pesi R, Allegrini S, Tozzi MG. Purine-Metabolising Enzymes and Apoptosis in Cancer. Cancers (Basel) 2019; 11:cancers11091354. [PMID: 31547393 PMCID: PMC6769685 DOI: 10.3390/cancers11091354] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/03/2019] [Accepted: 09/07/2019] [Indexed: 12/17/2022] Open
Abstract
The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5'-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5'-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.
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Affiliation(s)
- Marcella Camici
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy.
| | - Mercedes Garcia-Gil
- Dipartimento di Biologia, Unità di Fisiologia Generale, Via S. Zeno 31, 56127 Pisa, Italy
| | - Rossana Pesi
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy
| | - Simone Allegrini
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy
| | - Maria Grazia Tozzi
- Dipartimento di Biologia, Unità di Biochimica, Via S. Zeno 51, 56127 Pisa, Italy
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Borea PA, Gessi S, Merighi S, Vincenzi F, Varani K. Pharmacology of Adenosine Receptors: The State of the Art. Physiol Rev 2018; 98:1591-1625. [PMID: 29848236 DOI: 10.1152/physrev.00049.2017] [Citation(s) in RCA: 526] [Impact Index Per Article: 75.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A1, A2A, A2B, and A3. Due to the rapid generation of adenosine from cellular metabolism, and the widespread distribution of its receptor subtypes in almost all organs and tissues, this nucleoside induces a multitude of physiopathological effects, regulating central nervous, cardiovascular, peripheral, and immune systems. It is becoming clear that the expression patterns of adenosine receptors vary among cell types, lending weight to the idea that they may be both markers of pathologies and useful targets for novel drugs. This review offers an overview of current knowledge on adenosine receptors, including their characteristic structural features, molecular interactions and cellular functions, as well as their essential roles in pain, cancer, and neurodegenerative, inflammatory, and autoimmune diseases. Finally, we highlight the latest findings on molecules capable of targeting adenosine receptors and report which stage of drug development they have reached.
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Affiliation(s)
- Pier Andrea Borea
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Stefania Gessi
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Stefania Merighi
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Fabrizio Vincenzi
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
| | - Katia Varani
- Department of Medical Sciences, University of Ferrara , Ferrara , Italy
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Wang J, Matosevic S. Adenosinergic signaling as a target for natural killer cell immunotherapy. J Mol Med (Berl) 2018; 96:903-913. [PMID: 30069747 DOI: 10.1007/s00109-018-1679-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/27/2018] [Accepted: 07/25/2018] [Indexed: 01/21/2023]
Abstract
Purinergic signaling through adenosine plays a key role in immune regulation. Hypoxia-driven accumulation of extracellular adenosine results in the generation of an immunosuppressive niche that fuels tumor development. Such immunometabolic modulation has shown to be a promising therapeutic target through blockade of adenosine receptors which mediate adenosine's immunosuppressive function, or cancer-associated ectonucleotidases CD39 and CD73 that catalyze the synthesis of adenosine. Adenosinergic signaling heavily implicates natural killer cells through both direct and indirect effects on their cytolytic activity, expression of cytotoxic granules, interferon-γ, and activating receptors. Continuing work has uncovered multiple checkpoints linked to adenosine within the purinergic signaling cascade as contributing to immune evasion from NK cell effector function. Here, we discuss these checkpoints and the recent body of work that focuses on adenosinergic signaling as a target for natural killer cell of cancer.
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Affiliation(s)
- Jiao Wang
- Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, USA
| | - Sandro Matosevic
- Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, USA. .,Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
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10
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Jacobson KA, Merighi S, Varani K, Borea PA, Baraldi S, Tabrizi MA, Romagnoli R, Baraldi PG, Ciancetta A, Tosh DK, Gao ZG, Gessi S. A 3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy. Med Res Rev 2018; 38:1031-1072. [PMID: 28682469 PMCID: PMC5756520 DOI: 10.1002/med.21456] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 05/02/2017] [Accepted: 06/13/2017] [Indexed: 01/09/2023]
Abstract
The A3 adenosine receptor (A3 AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A3 AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A3 AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A3 AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A3 AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A3 AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A3 AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A3 AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.
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Affiliation(s)
- Kenneth A. Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD20892
| | - Stefania Merighi
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Katia Varani
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Pier Andrea Borea
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Stefania Baraldi
- Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
| | - Mojgan Aghazadeh Tabrizi
- Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
| | - Romeo Romagnoli
- Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
| | - Pier Giovanni Baraldi
- Department of Pharmaceutical Sciences, University of Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy
| | - Antonella Ciancetta
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD20892
| | - Dilip K. Tosh
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD20892
| | - Zhan-Guo Gao
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD20892
| | - Stefania Gessi
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy
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de Andrade Mello P, Coutinho-Silva R, Savio LEB. Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor-Host Interaction and Therapeutic Perspectives. Front Immunol 2017; 8:1526. [PMID: 29184552 PMCID: PMC5694450 DOI: 10.3389/fimmu.2017.01526] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 10/27/2017] [Indexed: 12/20/2022] Open
Abstract
Cancer is still one of the world's most pressing health-care challenges, leading to a high number of deaths worldwide. Immunotherapy is a new developing therapy that boosts patient's immune system to fight cancer by modifying tumor-immune cells interaction in the tumor microenvironment (TME). Extracellular adenosine triphosphate (eATP) and adenosine (Ado) are signaling molecules released in the TME that act as modulators of both immune and tumor cell responses. Extracellular adenosine triphosphate and Ado activate purinergic type 2 (P2) and type 1 (P1) receptors, respectively, triggering the so-called purinergic signaling. The concentration of eATP and Ado within the TME is tightly controlled by several cell-surface ectonucleotidases, such as CD39 and CD73, the major ecto-enzymes expressed in cancer cells, immune cells, stromal cells, and vasculature, being CD73 also expressed on tumor-associated fibroblasts. Once accumulated in the TME, eATP boosts antitumor immune response, while Ado attenuates or suppresses immunity against the tumor. In addition, both molecules can mediate growth stimulation or inhibition of the tumor, depending on the specific receptor activated. Therefore, purinergic signaling is able to modulate both tumor and immune cells behavior and, consequently, the tumor-host interaction and disease progression. In this review, we discuss the role of purinergic signaling in the host-tumor interaction detailing the multifaceted effects of eATP and Ado in the inflammatory TME. Moreover, we present recent findings into the application of purinergic-targeting therapy as a potential novel option to boost antitumor immune responses in cancer.
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Affiliation(s)
- Paola de Andrade Mello
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Robson Coutinho-Silva
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiz Eduardo Baggio Savio
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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12
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Kazemi MH, Raoofi Mohseni S, Hojjat-Farsangi M, Anvari E, Ghalamfarsa G, Mohammadi H, Jadidi-Niaragh F. Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer. J Cell Physiol 2017; 233:2032-2057. [DOI: 10.1002/jcp.25873] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 02/21/2017] [Indexed: 12/18/2022]
Affiliation(s)
- Mohammad H. Kazemi
- Student Research Committee, Department of Immunology, School of Medicine; Iran University of Medical Sciences (IUMS); Tehran Iran
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
| | - Sahar Raoofi Mohseni
- Department of Immunology, School of Public Health; Tehran University of Medical Sciences; Tehran Iran
| | - Mohammad Hojjat-Farsangi
- Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK); Karolinska University Hospital Solna and Karolinska Institute; Stockholm Sweden
- Department of Immunology, School of Medicine; Bushehr University of Medical Sciences; Bushehr Iran
| | - Enayat Anvari
- Faculty of Medicine, Department of Physiology; Ilam University of Medical Sciences; Ilam Iran
| | - Ghasem Ghalamfarsa
- Medicinal Plants Research Center; Yasuj University of Medical Sciences; Yasuj Iran
| | - Hamed Mohammadi
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Faculty of Medicine, Department of Immunology; Tabriz University of Medical Sciences; Tabriz Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Department of Immunology, School of Public Health; Tehran University of Medical Sciences; Tehran Iran
- Faculty of Medicine, Department of Immunology; Tabriz University of Medical Sciences; Tabriz Iran
- Drug Applied Research Center; Tabriz University of Medical Sciences; Tabriz Iran
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13
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Al-Taei S, Salimu J, Spary LK, Clayton A, Lester JF, Tabi Z. Prostaglandin E 2-mediated adenosinergic effects on CD14 + cells: Self-amplifying immunosuppression in cancer. Oncoimmunology 2016; 6:e1268308. [PMID: 28344879 DOI: 10.1080/2162402x.2016.1268308] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 11/25/2016] [Accepted: 11/29/2016] [Indexed: 01/14/2023] Open
Abstract
CD39 and CD73 are surface-expressed ectonucleotidases that hydrolyze ATP in a highly regulated, serial manner into ADP, AMP and adenosine. The end product, adenosine, has both tumor-promoting and immunosuppressive effects. The aim of this study was to determine CD73 expression on immune cells in pleural effusion (PE) in order to have a better understanding of the immune environment in mesothelioma. PE- or blood-derived CD14+ cells of mesothelioma patients and healthy donors were analyzed by flow cytometry for the expression of CD39 and CD73. CD73-induction was studied by exposure of CD14+ cells to the soluble fraction of PE (sPE), while the signaling mechanism, responsible for CD73 induction, by phosphoflow cytometry and receptor-inhibition studies. We observed CD73 expression on CD14+ cells in PE but not peripheral blood of mesothelioma patients or healthy donors. CD73 expression was inducible on CD14+ cells with sPE, cyclic-AMP (cAMP)-inducers (forskolin and prostaglandin-E2 (PGE2)) and adenosine. Inhibition of PGE2 receptors or adenosine A2 receptors blocked CD73-induction by sPE. sPE treatment triggered protein kinase A and p38 activation. However, signal-transducer and activator of transcription 3 (STAT3)-blocking led to enhanced CD73 expression, demonstrating a hitherto unknown negative control of purinergic signaling by STAT3 in CD14+ cells. TNFα production by CD73+ CD14+ cells was significantly impaired in the presence of AMP, confirming immunosuppressive function. Taken together, CD73 expression can be induced by PGE2, cAMP or adenosine on human CD14+ cells. We suggest that targeting this autocrine loop is a valid therapeutic approach in mesothelioma that may also enhance immunotherapy.
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Affiliation(s)
- Saly Al-Taei
- Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK
| | - Josephine Salimu
- Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK
| | - Lisa K Spary
- Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK
| | - Aled Clayton
- Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK
| | - Jason F Lester
- Velindre NHS Trust, Velindre Cancer Centre , Cardiff, UK
| | - Zsuzsanna Tabi
- Division of Cancer and Genetics, School of Medicine, Cardiff University , Cardiff, UK
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14
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Tsuchiya A, Nishizaki T. Anticancer effect of adenosine on gastric cancer via diverse signaling pathways. World J Gastroenterol 2015; 21:10931-10935. [PMID: 26494951 PMCID: PMC4607894 DOI: 10.3748/wjg.v21.i39.10931] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/11/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Extracellular adenosine induces apoptosis in a variety of cancer cells via intrinsic and extrinsic pathways. In the former pathway, adenosine uptake into cells triggers apoptosis, and in the latter pathway, adenosine receptors mediate apoptosis. Extracellular adenosine also induces apoptosis of gastric cancer cells. Extracellular adenosine is transported into cells through an adenosine transporter and converted to AMP by adenosine kinase. In turn, AMP activates AMP-activated protein kinase (AMPK). AMPK is the factor responsible for caspase-independent apoptosis of GT3-TKB gastric cancer cells. Extracellular adenosine, on the other hand, induces caspase-dependent apoptosis of MKN28 and MKN45 gastric cancer cells by two mechanisms. Firstly, AMP, converted from intracellularly transported adenosine, initiates apoptosis, regardless of AMPK. Secondly, the A3 adenosine receptor, linked to Gi/Gq proteins, mediates apoptosis by activating the Gq protein effector, phospholipase Cγ, to produce inositol 1,4,5-trisphosphate and diacylglycerol, which activate protein kinase C. Consequently, the mechanisms underlying adenosine-induced apoptosis vary, depending upon gastric cancer cell types. Understand the contribution of each downstream target molecule of adenosine to apoptosis induction may aid the establishment of tailor-made chemotherapy for gastric cancer.
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15
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Galvao J, Elvas F, Martins T, Cordeiro MF, Ambrósio AF, Santiago AR. Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration. Exp Eye Res 2015; 140:65-74. [PMID: 26297614 DOI: 10.1016/j.exer.2015.08.009] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 08/05/2015] [Accepted: 08/12/2015] [Indexed: 12/27/2022]
Abstract
Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A3 receptor (A3R) in neuroprotection is controversial, A3R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A3R activation against retinal neurodegeneration. The A3R selective agonist (2-Cl-IB-MECA, 1 μM) prevented apoptosis (TUNEL(+)-cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL(+)-cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL(+)-cells/mm(2) in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL(+) cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V(+)-cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo. Activation of A3R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases.
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Affiliation(s)
- Joana Galvao
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; Glaucoma & Retinal Neurodegeneration Research Group, University College London, London EC1V 9EL, UK.
| | - Filipe Elvas
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra 3000-548, Portugal.
| | - Tiago Martins
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra 3000-548, Portugal.
| | - M Francesca Cordeiro
- Glaucoma & Retinal Neurodegeneration Research Group, University College London, London EC1V 9EL, UK; Western Eye Hospital, Imperial College, London, UK.
| | - António Francisco Ambrósio
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra 3000-548, Portugal; CNC.IBILI, University of Coimbra, 3004-517 Coimbra, Portugal.
| | - Ana Raquel Santiago
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra 3000-548, Portugal; CNC.IBILI, University of Coimbra, 3004-517 Coimbra, Portugal.
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16
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Borea PA, Varani K, Vincenzi F, Baraldi PG, Tabrizi MA, Merighi S, Gessi S. The A3 adenosine receptor: history and perspectives. Pharmacol Rev 2015; 67:74-102. [PMID: 25387804 DOI: 10.1124/pr.113.008540] [Citation(s) in RCA: 198] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
By general consensus, the omnipresent purine nucleoside adenosine is considered a major regulator of local tissue function, especially when energy supply fails to meet cellular energy demand. Adenosine mediation involves activation of a family of four G protein-coupled adenosine receptors (ARs): A(1), A(2)A, A(2)B, and A(3). The A(3) adenosine receptor (A(3)AR) is the only adenosine subtype to be overexpressed in inflammatory and cancer cells, thus making it a potential target for therapy. Originally isolated as an orphan receptor, A(3)AR presented a twofold nature under different pathophysiologic conditions: it appeared to be protective/harmful under ischemic conditions, pro/anti-inflammatory, and pro/antitumoral depending on the systems investigated. Until recently, the greatest and most intriguing challenge has been to understand whether, and in which cases, selective A(3) agonists or antagonists would be the best choice. Today, the choice has been made and A(3)AR agonists are now under clinical development for some disorders including rheumatoid arthritis, psoriasis, glaucoma, and hepatocellular carcinoma. More specifically, the interest and relevance of these new agents derives from clinical data demonstrating that A(3)AR agonists are both effective and safe. Thus, it will become apparent in the present review that purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health.
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Affiliation(s)
- Pier Andrea Borea
- Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
| | - Katia Varani
- Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
| | - Fabrizio Vincenzi
- Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
| | - Pier Giovanni Baraldi
- Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
| | - Mojgan Aghazadeh Tabrizi
- Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
| | - Stefania Merighi
- Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
| | - Stefania Gessi
- Department of Medical Sciences, Pharmacology Section (P.A.B., K.V., F.V., S.M., S.G.), and Department of Pharmaceutical Sciences, University of Ferrara, Italy (P.G.B., M.A.T.)
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17
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Mikami K, Nagaya H, Gotoh A, Kanno T, Tsuchiya A, Nakano T, Nishizaki T. Naftopidil is useful for the treatment of malignant pleural mesothelioma. Pharmacology 2014; 94:163-9. [PMID: 25301502 DOI: 10.1159/000368050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 08/29/2014] [Indexed: 11/19/2022]
Abstract
Naftopidil, an α1-adrenoceptor blocker, induced apoptosis of human malignant pleural mesothelioma NCI-H2052 cells. Naftopidil upregulated the expression of tumor necrosis factor-α (TNF-α) mRNA in these cells. Naftopidil, alternatively, increased FasL secretion from NCI-H2052 cells, without affecting the expression of FasL mRNA and protein, and activated caspase-3 and -8 in NCI-H2052 cells. Naftopidil drastically suppressed tumor growth in mice inoculated with these cells. The results of the present study indicate that naftopidil induces apoptosis of NCI-H2052 cells by upregulating the expression of TNF-α and stimulating the secretion of FasL, a ligand for the death receptor Fas, both to activate caspase-8 and the effector caspase-3, leading to the suppression of NCI-H2052 cell proliferation in vivo. This raises the possibility that naftopidil could be developed as an effective drug for the treatment of malignant pleural mesothelioma.
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Affiliation(s)
- Koji Mikami
- Division of Respiratory Medicine, Department of Internal Medicine, Nishinomiya, Japan
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18
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Mello PDA, Filippi-Chiela EC, Nascimento J, Beckenkamp A, Santana DB, Kipper F, Casali EA, Nejar Bruno A, Paccez JD, Zerbini LF, Wink MR, Lenz G, Buffon A. Adenosine uptake is the major effector of extracellular ATP toxicity in human cervical cancer cells. Mol Biol Cell 2014; 25:2905-18. [PMID: 25103241 PMCID: PMC4230581 DOI: 10.1091/mbc.e14-01-0042] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
In cervical cancer, HPV infection and disruption of mechanisms involving cell growth, differentiation, and apoptosis are strictly linked with tumor progression and invasion. Tumor microenvironment is ATP and adenosine rich, suggesting a role for purinergic signaling in cancer cell growth and death. Here we investigate the effect of extracellular ATP on human cervical cancer cells. We find that extracellular ATP itself has a small cytotoxic effect, whereas adenosine formed from ATP degradation by ectonucleotidases is the main factor responsible for apoptosis induction. The level of P2 × 7 receptor seemed to define the main cytotoxic mechanism triggered by ATP, since ATP itself eliminated a small subpopulation of cells that express high P2 × 7 levels, probably through its activation. Corroborating these data, blockage or knockdown of P2 × 7 only slightly reduced ATP cytotoxicity. On the other hand, cell viability was almost totally recovered with dipyridamole, an adenosine transporter inhibitor. Moreover, ATP-induced apoptosis and signaling-p53 increase, AMPK activation, and PARP cleavage-as well as autophagy induction were also inhibited by dipyridamole. In addition, inhibition of adenosine conversion into AMP also blocked cell death, indicating that metabolization of intracellular adenosine originating from extracellular ATP is responsible for the main effects of the latter in human cervical cancer cells.
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Affiliation(s)
- Paola de Andrade Mello
- Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil
| | - Eduardo Cremonese Filippi-Chiela
- Department of Biophysics and Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS 91501-970, Brazil
| | - Jéssica Nascimento
- Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil
| | - Aline Beckenkamp
- Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil
| | - Danielle Bertodo Santana
- Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil
| | - Franciele Kipper
- Department of Biophysics and Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS 91501-970, Brazil
| | - Emerson André Casali
- Department of Morphological Science and Department of Biochemistry, Institute of Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS 90000-000, Brazil
| | - Alessandra Nejar Bruno
- Federal Institute of Education, Science and Technology, Porto Alegre, RS 90035-007, Brazil
| | - Juliano Domiraci Paccez
- International Center for Genetic Engineering and Biotechnology, Cancer Genomics Group, Cape Town 7925, South Africa
| | - Luiz Fernando Zerbini
- International Center for Genetic Engineering and Biotechnology, Cancer Genomics Group, Cape Town 7925, South Africa
| | - Marcia Rosângela Wink
- Laboratory of Cell Biology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS 90050-170, Brazil
| | - Guido Lenz
- Department of Biophysics and Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS 91501-970, Brazil
| | - Andréia Buffon
- Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil
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19
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Virtanen SS, Kukkonen-Macchi A, Vainio M, Elima K, Härkönen PL, Jalkanen S, Yegutkin GG. Adenosine inhibits tumor cell invasion via receptor-independent mechanisms. Mol Cancer Res 2014; 12:1863-74. [PMID: 25080434 DOI: 10.1158/1541-7786.mcr-14-0302-t] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Extracellular adenosine mediates diverse anti-inflammatory, angiogenic, and other signaling effects via binding to adenosine receptors, and it also regulates cell proliferation and death via activation of the intrinsic signaling pathways. Given the emerging role of adenosine and other purines in tumor growth and metastasis, this study evaluated the effects of adenosine on the invasion of metastatic prostate and breast cancer cells. Treatment with low micromolar concentrations of adenosine, but not other nucleosides or adenosine receptor agonists, inhibited subsequent cell invasion and migration through Matrigel- and laminin-coated inserts. These inhibitory effects occurred via intrinsic receptor-independent mechanisms, despite the abundant expression of A2B adenosine receptors (ADORA2B). Extracellular nucleotides and adenosine were shown to be rapidly metabolized on tumor cell surfaces via sequential ecto-5'-nucleotidase (CD73/NT5E) and adenosine deaminase reactions with subsequent cellular uptake of nucleoside metabolites and their intracellular interconversion into ADP/ATP. This was accompanied by concurrent inhibition of AMP-activated protein kinase and other signaling pathways. No differences in the proliferation rates, cytoskeleton assembly, expression of major adhesion molecules [integrin-1β (ITGB1), CD44, focal adhesion kinase], and secretion of matrix metalloproteinases were detected between the control and treated cells, thus excluding the contribution of these components of invasion cascade to the inhibitory effects of adenosine. These data provide a novel insight into the ability of adenosine to dampen immune responses and prevent tumor invasion via two different, adenosine receptor-dependent and -independent mechanisms. IMPLICATIONS This study suggests that the combined targeting of adenosine receptors and modulation of intracellular purine levels can affect tumor growth and metastasis phenotypes.
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Affiliation(s)
- Sanna S Virtanen
- Turku University of Applied Sciences, University of Turku, Turku, Finland. Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
| | | | - Minna Vainio
- Department of Biology, University of Turku, Turku, Finland
| | - Kati Elima
- Department of Medical Microbiology, University of Turku, Turku, Finland
| | - Pirkko L Härkönen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
| | - Sirpa Jalkanen
- Department of Medical Microbiology, University of Turku, Turku, Finland
| | - Gennady G Yegutkin
- Department of Medical Microbiology, University of Turku, Turku, Finland.
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20
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Tsuchiya A, Kanno T, Nishizaki T. Adenosine exerts potent anticancer effects through diverse signaling pathways. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.pmu.2014.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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21
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Krześniak M, Zajkowicz A, Matuszczyk I, Rusin M. Rapamycin prevents strong phosphorylation of p53 on serine 46 and attenuates activation of the p53 pathway in A549 lung cancer cells exposed to actinomycin D. Mech Ageing Dev 2014; 139:11-21. [DOI: 10.1016/j.mad.2014.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 05/27/2014] [Accepted: 06/01/2014] [Indexed: 12/24/2022]
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22
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Cordycepin induces apoptosis of C6 glioma cells through the adenosine 2A receptor-p53-caspase-7-PARP pathway. Chem Biol Interact 2014; 216:17-25. [DOI: 10.1016/j.cbi.2014.03.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 03/14/2014] [Accepted: 03/26/2014] [Indexed: 11/18/2022]
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23
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Antonioli L, Blandizzi C, Pacher P, Haskó G. Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer 2013; 13:842-857. [PMID: 24226193 DOI: 10.1038/nrc3613] [Citation(s) in RCA: 576] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in regulating the complex interplay among immune, inflammatory, endothelial and cancer cells during the course of neoplastic disease.
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Affiliation(s)
- Luca Antonioli
- 1] Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy. [2] Department of Surgery and Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA
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24
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Kanno T, Tanaka A, Shimizu T, Nakano T, Nishizaki T. 1-[2-(2-Methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol as a potential anticancer drug. Pharmacology 2013; 91:339-45. [PMID: 23817168 DOI: 10.1159/000351747] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 03/22/2013] [Indexed: 01/08/2023]
Abstract
The aim of the present study was to assess the anticancer effect of several naftopidil analogues on human malignant mesothelioma cell lines NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H, human lung cancer cell lines A549, SBC-3, and Lu-65, human hepatoma cell lines HepG2 and HuH-7, human gastric cancer cell lines MKN-28 and MKN-45, and human bladder cancer cell lines 253J, 5637, KK-47, TCCSUP, T24, and UM-UC-3, human prostate cancer cell lines DU145, LNCap, and PC-3, and human renal cancer cell lines ACHN, RCC4-VHL, and 786-O. We newly synthesized 21 naftopidil analogues, and of them 1-[2-(2-methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol (HUHS1015) most efficiently reduced cell viability for all the investigated malignant mesothelioma cell lines in a concentration (1-100 μmol/l)-dependent manner. HUHS1015 reduced cell viability for all other investigated cancer cell lines, to an extent similar to that for malignant mesothelioma cell lines. HUHS1015 activated caspase-3 and -4, without activating caspase-8 and -9, in malignant mesothelioma cell lines. The results of the present study, thus, indicate that HUHS1015 induces apoptosis in a variety of cancer cells, possibly by activating caspase-4 and the effector caspase-3.
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Affiliation(s)
- Takeshi Kanno
- Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan
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25
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Kanno T, Gotoh A, Fujita Y, Nakano T, Nishizaki T. A(3) adenosine receptor mediates apoptosis in 5637 human bladder cancer cells by G(q) protein/PKC-dependent AIF upregulation. Cell Physiol Biochem 2012; 30:1159-68. [PMID: 23171836 DOI: 10.1159/000343306] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS A(3) adenosine receptor mediates apoptosis in a variety of cancer cells via diverse signaling pathways. The present study was conducted to assess A(3) adenosine receptor-mediated apoptosis in human bladder cancer cell lines and to understand the underlying mechanism. METHODS Human bladder cancer cell lines such as 253J, 5637, KK-47, TCCSUP, T24, and UMUC-3 cells were cultured. The siRNA to silence the A(3) adenosine receptor-targeted gene was constructed and transfected into cells. MTT assay, TUNEL staining, Western blotting, and real-time RT-PCR were carried out. RESULTS For all the investigated cell types adenosine induced apoptosis in a concentration (0.01-10 mM)- and treatment time (24-48 h)-dependent manner. Adenosine-induced 5637 cell death was significantly inhibited by the A(3) adenosine receptor inhibitor MRS1191 or knocking-down A(3) adenosine receptor, and the A(3) adenosine receptor agonist 2-Cl-IB-MECA mimicked the adenosine effect. The adenosine effect was prevented by GF109203X, an inhibitor of protein kinase C (PKC), but it was not affected by forskolin, an activator of adenylate cyclase. Adenosine-induced 5637 cell death, alternatively, was not inhibited by the pan-caspase inhibitor Z-VAD. Adenosine upregulated expression of apoptosis-inducing factor (AIF), that is suppressed by knocking-down A(3) adenosine receptor, and accumulated AIF in the nucleus. CONCLUSION The results of the present study show that adenosine induces 5637 cell apoptosis by upregulating AIF expression via an A(3) adenosine receptor-mediated G(q) protein/PKC pathway.
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Affiliation(s)
- Takeshi Kanno
- Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan
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