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Gan M, Liu N, Li W, Chen M, Bai Z, Liu D, Liu S. Metabolic targeting of regulatory T cells in oral squamous cell carcinoma: new horizons in immunotherapy. Mol Cancer 2024; 23:273. [PMID: 39696340 DOI: 10.1186/s12943-024-02193-7] [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: 09/23/2024] [Accepted: 12/03/2024] [Indexed: 12/20/2024] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent oral malignancy, which poses significant health risks with a high mortality rate. Regulatory T cells (Tregs), characterized by their immunosuppressive capabilities, are intricately linked to OSCC progression and patient outcomes. The metabolic reprogramming of Tregs within the OSCC tumor microenvironment (TME) underpins their function, with key pathways such as the tryptophan-kynurenine-aryl hydrocarbon receptor, PI3K-Akt-mTOR and nucleotide metabolism significantly contributing to their suppressive activities. Targeting these metabolic pathways offers a novel therapeutic approach to reduce Treg-mediated immunosuppression and enhance anti-tumor responses. This review explores the metabolic dependencies and pathways that sustain Treg function in OSCC, highlighting key metabolic adaptations such as glycolysis, fatty acid oxidation, amino acid metabolism and PI3K-Akt-mTOR signaling pathway that enable Tregs to thrive in the challenging conditions of the TME. Additionally, the review discusses the influence of the oral microbiome on Treg metabolism and evaluates potential therapeutic strategies targeting these metabolic pathways. Despite the promising potential of these interventions, challenges such as selectivity, toxicity, tumor heterogeneity, and resistance mechanisms remain. The review concludes with perspectives on personalized medicine and integrative approaches, emphasizing the need for continued research to translate these findings into effective clinical applications for OSCC treatment.
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Affiliation(s)
- Menglai Gan
- Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, Liaoning, China
| | - Nanshu Liu
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, Liaoning, China
| | - Wenting Li
- Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, Liaoning, China
| | - Mingwei Chen
- Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, Liaoning, China
| | - Zhongyu Bai
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, Liaoning, China
| | - Dongjuan Liu
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, Liaoning, China.
| | - Sai Liu
- Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, Liaoning, China.
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Pandey S, Anang V, Schumacher MM. Tumor microenvironment induced switch to mitochondrial metabolism promotes suppressive functions in immune cells. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 389:67-103. [PMID: 39396850 DOI: 10.1016/bs.ircmb.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Understanding the intricacies of the metabolic phenotype in immune cells and its plasticity within the tumor microenvironment is pivotal in understanding the pathology and prognosis of cancer. Unfavorable conditions and cellular stress in the tumor microenvironment (TME) exert a profound impact on cellular functions in immune cells, thereby influencing both tumor progression and immune responses. Elevated AMP:ATP ratio, a consequence of limited glucose levels, activate AMP-activated protein kinase (AMPK) while concurrently repressing the activity of mechanistic target of rapamycin (mTOR) and hypoxia-inducible factor 1-alpha (HIF-1α). The intricate balance between AMPK, mTOR, and HIF-1α activities defines the metabolic phenotype of immune cells in the TME. These Changes in metabolic phenotype are strongly associated with immune cell functions and play a crucial role in creating a milieu conducive to tumor progression. Insufficiency of nutrient and oxygen supply leads to a metabolic shift in immune cells characterized by a decrease in glycolysis and an increase in oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) rates. In most cases, this shift in metabolism is accompanied by a compromise in the effector functions of these immune cells. This metabolic adaptation prompts immune cells to turn down their effector functions, entering a quiescent or immunosuppressive state that may support tumor growth. This article discusses how tumor microenvironment alters the metabolism in immune cells leading to their tolerance and tumor progression, with emphasis on mitochondrial metabolism (OXPHOS and FAO).
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Affiliation(s)
- Sanjay Pandey
- Department of Radiation Oncology, Montefiorke Medical Center, Bronx, NY, United States.
| | - Vandana Anang
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
| | - Michelle M Schumacher
- Department of Radiation Oncology, Montefiorke Medical Center, Bronx, NY, United States; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States
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Pandey S, Anang V, Singh S, Seth S, Bhatt AN, Kalra N, Manda K, Soni R, Roy BG, Natarajan K, Dwarakanath BS. Dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose reduces endotoxemia-induced inflammation and oxidative stress: Implications in PAMP-associated acute and chronic pathology. Front Pharmacol 2023; 14:940129. [PMID: 37234710 PMCID: PMC10206263 DOI: 10.3389/fphar.2023.940129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 04/20/2023] [Indexed: 05/28/2023] Open
Abstract
Pathogen-associated molecular patterns (PAMPs) like bacterial cell wall components and viral nucleic acids are known ligands of innate inflammatory receptors that trigger multiple inflammatory pathways that may result in acute inflammation and oxidative stress-driven tissue and organ toxicity. When dysregulated, this inflammation may lead to acute toxicity and multiorgan failure. Inflammatory events are often driven by high energy demands and macromolecular biosynthesis. Therefore, we proposed that targeting the metabolism of lipopolysaccharide (LPS)-driven inflammatory events, using an energy restriction approach, can be an effective strategy to prevent the acute or chronic detrimental effects of accidental or seasonal bacterial and other pathogenic exposures. In the present study, we investigated the potential of energy restriction mimetic agent (ERMA) 2-deoxy-D-glucose (2-DG) in targeting the metabolism of inflammatory events during LPS-elicited acute inflammatory response. Mice fed with 2-DG as a dietary component in drinking water showed reduced LPS-driven inflammatory processes. Dietary 2-DG reduced LPS-induced lung endothelial damage and oxidative stress by strengthening the antioxidant defense system and limiting the activation and expression of inflammatory proteins, viz., P-Stat-3, NfκΒ, and MAP kinases. This was accompanied by decreased TNF, IL-1β, and IL-6 levels in peripheral blood and bronchoalveolar lavage fluid (BALF). 2-DG also reduced the infiltration of PMNCs (polymorphonuclear cells) in inflamed tissues. Altered glycolysis and improved mitochondrial activity in 2-DG-treated RAW 264.7 macrophage cells suggested possible impairment of macrophage metabolism and, therefore, activation in macrophages. Taken together, the present study suggests that inclusion of glycolytic inhibitor 2-DG as a part of the diet can be helpful in preventing the severity and poor prognosis associated with inflammatory events during bacterial and other pathogenic exposures.
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Affiliation(s)
- Sanjay Pandey
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
- Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Vandana Anang
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Saurabh Singh
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
- Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Saurabh Seth
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Anant Narayan Bhatt
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Namita Kalra
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Kailash Manda
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Ravi Soni
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Bal Gangadhar Roy
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - K. Natarajan
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Bilikere S. Dwarakanath
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
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Vashishta M, Kumar V, Guha C, Wu X, Dwarakanath BS. Enhanced Glycolysis Confers Resistance Against Photon but Not Carbon Ion Irradiation in Human Glioma Cell Lines. Cancer Manag Res 2023; 15:1-16. [PMID: 36628255 PMCID: PMC9826608 DOI: 10.2147/cmar.s385968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 12/17/2022] [Indexed: 01/05/2023] Open
Abstract
Purpose Metabolic reprogramming is a key hallmark in various malignancies and poses a challenge in achieving success with various therapies. Enhanced glycolysis is known to confer resistance against photon irradiation while the tumor response to carbon ion irradiation (CII) has not been investigated. This study aimed to investigate the effects of enhanced glycolysis on the response of human glioma cell lines to CII compared to the response to X-rays. Material and Methods Glycolysis was stimulated using Dinitrophenol (DNP), a mild OXPHOS inhibitor, in three human glioma cell lines (U251, U87, and LN229) and assessed by monitoring glucose uptake and utilization as well as expression of regulators of glycolysis (glucose transporter protein type 1(Glut1), hexokinase-II (HKII), and Pyruvate Kinase-2 (PKM2). Radiation (X-rays and CII) induced loss of clonogenic survival growth inhibition and perturbations in cell cycle progression (G2+M block), cytogenetic damage (micronuclei formation), apoptosis, necrosis (reflecting interphase death), and cell migration (Scratch assay) were investigated as parameters of radiation response. Results DNP (1 mM) enhanced the expression levels of GLUT1, HKII, and PKM2 by 30-60% and glucose uptake as well as usage by nearly 3 folds in U251 cells suggesting the stimulation of glycolysis. Enhanced glycolysis attenuated the loss of clonogenic survival with D10 doses increasing by 20% to 65% in these cell lines, while no significant changes were noted following CII. Concomitantly, dose-dependent growth inhibition, and cytogenetic damage as well as apoptosis and necrosis induced by X-rays were also reduced by elevated glycolysis in U251 and LN229 cells by 20-50%. However, stimulation of glycolysis enhanced the X-ray-induced cell migration, while it had negligible effect on migration following CII. Conclusion Our results suggest that enhanced glycolysis confers resistance against X-ray-induced cell death and migration, while it may not significantly alter the cellular responses to carbon ion irradiation.
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Affiliation(s)
- Mohit Vashishta
- R&D Department, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, People’s Republic of China,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China,Rangel College of Pharmacy, Texas A&M University, College Station, TX, USA
| | - Vivek Kumar
- R&D Department, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, People’s Republic of China,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China
| | - Chandan Guha
- Albert Einstein College of Medicine, The Bronx, NY, USA
| | - Xiaodong Wu
- R&D Department, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, People’s Republic of China,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China
| | - Bilikere S Dwarakanath
- R&D Department, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, People’s Republic of China,Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China,Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China,Central Research Facility, Sri Ramachandra Institute of Higher Education and Research, Porur, ChennaiIndia,Indian Academy Degree College Autonomous (IADC-A), Bengaluru, Karnataka, India,Correspondence: Bilikere S Dwarakanath, Indian Academy Degree College Autonomous (IADC-A), 230, Hennur Main Rd, Meganahalli, Kalyan Nagar, Bengaluru, Karnataka, 560043, India, Tel +91 9952081077, Email
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Ahmed I, Verma A, Umar S, Papineni RVL. 2-deoxy-D-glucose mitigates Citrobacter rodentium and dibenzazepine-induced gastrointestinal damage and colitis: novel implications of 2-DG polypharmacopea. Int J Radiat Biol 2023; 99:681-691. [PMID: 35946994 DOI: 10.1080/09553002.2022.2110297] [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: 10/15/2022]
Abstract
PURPOSE Citrobacter rodentium (CR) infection coupled with blocking Notch/Wnt signaling via γ-secretase inhibitor dibenzazepine (DBZ) disrupts the gastro-intestinal (GI) barrier and induces colitis, akin to ionizing radiation (IR)-induced GI-injury. We investigated the effects of 2-deoxy-D-glucose (2-DG) to ameliorate the CR-DBZ-induced GI damage. MATERIALS AND METHODS NIH:Swiss outbred mice were inoculated with 109CFUs of CR orally. DBZ was administered intraperitoneally (10 μM/kg b.wt; for 10 days 2 days post-CR infection). Mice were fed with 0.4% 2-DG (w/v) daily in drinking water. For microbiota depletion, antibiotics (Abx), 1 g/l metronidazole, and 0.2 g/l ciprofloxacin were administered for 10 days in drinking water. Oxidative stress, survival assay, colonic crypt hyperplasia, Notch/Wnt downstream signaling, immunomodulation, and bacterial dysbiosis were measured. RESULTS We show that real-time visualization of reactive oxygen species (ROS) is similar during CR-induced colonic infection and IR-induced GI-damage. The histology revealed that dietary 2-DG mitigates CR + DBZ-induced colitis and improves survival compared with CR + DBZ alone. These changes were phenocopied in Abx-treated mice. Both 2-DG and Abx reduced dysbiosis, increased proliferation, inhibited pro-inflammatory response, and restored Hes-1 and β-catenin protein levels, in the crypts. CONCLUSION The energy disruptor 2-DG mitigates bacterial infection and its responsive hyperplasia/colitis, indicating its utility as a mitigator of infection/IR-induced GI-damage.
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Affiliation(s)
- Ishfaq Ahmed
- Department of Surgery, University of Kansas, Medical Center, Kansas City, KS, USA
| | | | - Shahid Umar
- Department of Surgery, University of Kansas, Medical Center, Kansas City, KS, USA
| | - Rao V L Papineni
- Department of Surgery, University of Kansas, Medical Center, Kansas City, KS, USA
- PACT & Health LLC, Branford, CT, USA
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Guo Y, Sun D, Zhang Y, Yu X, Fang Y, Lv C, Zhang Q, Zhu Y, Qiao S, Xia Y, Wei Z, Dai Y. The neuropeptide cortistatin attenuates Th17 cell response through inhibition of glycolysis via GHSR1. Int Immunopharmacol 2022; 108:108843. [DOI: 10.1016/j.intimp.2022.108843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/18/2022] [Accepted: 05/04/2022] [Indexed: 11/27/2022]
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Ghosh R, Roy D, Chatterjee S, Benito-León J. 2-deoxy-D-glucose as India's Response to COVID-19: A Commitment or Conceit? J Community Hosp Intern Med Perspect 2022; 12:53-56. [PMID: 35711390 PMCID: PMC9195081 DOI: 10.55729/2000-9666.1052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 12/16/2021] [Indexed: 11/23/2022] Open
Abstract
2-deoxy-d-glucose (2-DG) has recently been approved for the treatment of moderate to severe COVID-19 patients in India. Here we discuss whether this is a well-thought-out step towards the long-term management of COVID-19 or a decision taken at the spur of the moment. 2-DG, an anticancer drug, also has immunomodulatory functions. Several studies have shown 2-DG to inhibit viral replication and cytokine storm. However, these findings are mostly on cells and animal models. The clinical trial that has become the basis of the approval of this drug in India is yet to be peer-reviewed and has not explicitly addressed several concerns, nor has it established its claim of faster efficacy with rigorous statistics and safety profile. Even though 2-DG shows much promise in COVID-19 treatment, its approval seems rather premature, which may prove to be more harmful than beneficial in the long run.
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Affiliation(s)
- Ritwik Ghosh
- Department of General Medicine, Burdwan Medical College & Hospital, Burdwan, West Bengal,
India
| | - Dipayan Roy
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Jodhpur, Rajasthan,
India
| | - Subhankar Chatterjee
- Department of Internal Medicine, Patliputra Medical College and Hospital, Dhanbad, Jharkhand,
India
| | - Julián Benito-León
- Department of Neurology, University Hospital “12 de Octubre”, Madrid,
Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid,
Spain
- Department of Medicine, Complutense University, Madrid,
Spain
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Santos AF, Póvoa P, Paixão P, Mendonça A, Taborda-Barata L. Changes in Glycolytic Pathway in SARS-COV 2 Infection and Their Importance in Understanding the Severity of COVID-19. Front Chem 2021; 9:685196. [PMID: 34568275 PMCID: PMC8461303 DOI: 10.3389/fchem.2021.685196] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/31/2021] [Indexed: 12/21/2022] Open
Abstract
COVID-19 is an infectious disease caused by Coronavirus 2 (SARS-CoV-2) that may lead to a severe acute respiratory syndrome. Such syndrome is thought to be related, at least in part, to a dysregulation of the immune system which involves three main components: hyperactivity of the innate immune system; decreased production of type 1 Interferons (IFN) by SARS-CoV-2-infected cells, namely respiratory epithelial cells and macrophages; and decreased numbers of both CD4+ and particularly CD8+ T cells. Herein, we describe how excessive activation of the innate immune system and the need for viral replication in several cells of the infected organism promote significant alterations in cells' energy metabolism (glucose metabolism), which may underlie the poor prognosis of the disease in severe situations. When activated, cells of the innate immune system reprogram their metabolism, and increase glucose uptake to ensure secretion of pro-inflammatory cytokines. Changes in glucose metabolism are also observed in pulmonary epithelial cells, contributing to dysregulation of cytokine synthesis and inflammation of the pulmonary epithelium. Controlling hyperglycolysis in critically ill patients may help to reduce the exaggerated production of pro-inflammatory cytokines and optimise the actions of the adaptive immune system. In this review, we suggest that the administration of non-toxic concentrations of 2-deoxy-D-glucose, the use of GLUT 1 inhibitors, of antioxidants such as vitamin C in high doses, as well as the administration of N-acetylcysteine in high doses, may be useful complementary therapeutic strategies for these patients, as suggested by some clinical trials and/ or reports. Overall, understanding changes in the glycolytic pathway associated with COVID-19 infection can help to find new forms of treatment for this disease.
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Affiliation(s)
- Adalberto Fernandes Santos
- Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
- CICS-UBI Health Sciences Research Centre, Universidade da Beira Interior, Lisbon, Portugal
- Department of Teaching and Research of Biochemistry, Faculty of Medicine, Agostinho Neto University, Luanda, Angola
| | - Pedro Póvoa
- Polyvalent Intensive Care Unit, Centro Hospitalar de Lisboa Ocidental, Hospital de Sao Francisco Xavier, Lisbon, Portugal
- Comprehensive Health Research Center–CHRC, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
- Center for Clinical Epidemiology and Research Unit of Clinical Epidemiology, OUH Odense University Hospital, Odense, Denmark
| | - Paulo Paixão
- Comprehensive Health Research Center–CHRC, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
- Laboratório de Patologia Clínica–SYNLAB, Hospital da Luz, Lisbon, Portugal
| | - António Mendonça
- CICS-UBI Health Sciences Research Centre, Universidade da Beira Interior, Lisbon, Portugal
- Department of Chemistry, Faculty of Sciences, University of Beira Interior, Covilhã, Portugal
| | - Luís Taborda-Barata
- Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
- CICS-UBI Health Sciences Research Centre, Universidade da Beira Interior, Lisbon, Portugal
- Department of Immunoallergology, Cova da Beira University Hospital Centre, Covilhã, Portugal
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Verma A, Adhikary A, Woloschak G, Dwarakanath BS, Papineni RVL. A combinatorial approach of a polypharmacological adjuvant 2-deoxy-D-glucose with low dose radiation therapy to quell the cytokine storm in COVID-19 management. Int J Radiat Biol 2020; 96:1323-1328. [PMID: 32910699 DOI: 10.1080/09553002.2020.1818865] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease and is the major cause of deaths worldwide. The clinical complexities (inflammation, cytokine storm, and multi-organ dysfunction) associated with COVID-19 poses constraints to effective management of critically ill COVID-19 patients. Low dose radiation therapy (LDRT) has been evaluated as a potential therapeutic modality for COVID-19 pneumonia. However, due to heterogeneity in disease manifestation and inter-individual variations, effective planning for LDRT is limited for this large-scale event. 2-deoxy-D-glucose (2-DG) has emerged as a polypharmacological agent for COVID-19 treatment due to its effects on the glycolytic pathway, anti-inflammatory action, and interaction with viral proteins. We suggest that 2-DG will be a potential adjuvant to enhance the efficacy of LDRT in the treatment of COVID-19 pneumonia. Withal, azido analog of 2-DG, 2-azido-2-DG can produce rapid catastrophic oxidative stress and quell the cytokine storm in critically ill COVID-19 patients.
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Affiliation(s)
| | | | - Gayle Woloschak
- Department of Radiobiology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA
| | - Bilikere S Dwarakanath
- Department of Research and Development, Shanghai Proton and Heavy Ion Center, Shanghai, People's Republic of China
| | - Rao V L Papineni
- Department of Surgery, University of Kansas Medical Center (Adjunct), and PACT & Health LLC, Branford, CT, USA
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Gupta S, Dwarakanath BS. Modulation of Immuno-biome during Radio-sensitization of Tumors by Glycolytic Inhibitors. Curr Med Chem 2020; 27:4002-4015. [PMID: 29852858 DOI: 10.2174/0929867325666180601101145] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/15/2018] [Accepted: 01/24/2018] [Indexed: 12/12/2022]
Abstract
The Tumor Microenvironment (TME) comprising stromal cells, fibroblasts and various components of the immune system forms a pro-tumorigenic cocoon around the tumor cells with the reprogramming of the metabolism in the form of Warburg phenotype (enhanced aerobic glycolysis) in tumor as well as non-tumor cells. This reprogramming plays a significant role in suppressing the immune response leading to the survival and proliferation of tumor cells and resistance to therapies. Therefore, there is a considerable interest in developing strategies involving metabolic modifiers to improve the therapeutic efficacy that restores immune competence, besides enhancing the direct effects on tumor cells. Inhibitors of glycolysis like 2-deoxy-D-glucose (2-DG; a hexokinase inhibitor), dichloroacetate and small molecule inhibitors of lactate transport (MCT-1) are some of the metabolic modifiers investigated for their therapeutic as well as adjuvant potential. Among these, 2-DG has been widely investigated and established as an ideal adjuvant in the radio- and chemotherapy of tumors. Modulation of the immuno-biome in the form of cytokine shifts, differential transcriptional regulation, abrogation of immunosuppressive network and reduced accumulation of lactate are some of the contributing factors for immune stimulation linked to the radio- and chemosensitization by glycolytic inhibitors.
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Affiliation(s)
- Seema Gupta
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20007, United States
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Huang J, Li JJ. Multiple Dynamics in Tumor Microenvironment Under Radiotherapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1263:175-202. [PMID: 32588328 DOI: 10.1007/978-3-030-44518-8_10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The tumor microenvironment (TME) is an evolutionally low-level and embryonically featured tissue comprising heterogenic populations of malignant and stromal cells as well as noncellular components. Under radiotherapy (RT), the major modality for the treatment of malignant diseases [1], TME shows an adaptive response in multiple aspects that affect the efficacy of RT. With the potential clinical benefits, interests in RT combined with immunotherapy (IT) are intensified with a large scale of clinical trials underway for an array of cancer types. A better understanding of the multiple molecular aspects, especially the cross talks of RT-mediated energy reprogramming and immunoregulation in the irradiated TME (ITME), will be necessary for further enhancing the benefit of RT-IT modality. Coming studies should further reveal more mechanistic insights of radiation-induced instant or permanent consequence in tumor and stromal cells. Results from these studies will help to identify critical molecular pathways including cancer stem cell repopulation, metabolic rewiring, and specific communication between radioresistant cancer cells and the infiltrated immune active lymphocytes. In this chapter, we will focus on the following aspects: radiation-repopulated cancer stem cells (CSCs), hypoxia and re-oxygenation, reprogramming metabolism, and radiation-induced immune regulation, in which we summarize the current literature to illustrate an integrated image of the ITME. We hope that the contents in this chapter will be informative for physicians and translational researchers in cancer radiotherapy or immunotherapy.
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Affiliation(s)
- Jie Huang
- Department of Radiation Oncology, University of California Davis, Sacramento, CA, USA
| | - Jian Jian Li
- Department of Radiation Oncology, University of California Davis, Sacramento, CA, USA. .,NCI-Designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
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12
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Lee AK, Pan D, Bao X, Hu M, Li F, Li CY. Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy. Radiat Res 2020; 193:305-317. [PMID: 32074012 DOI: 10.1667/rade-20-00013] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.
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Affiliation(s)
- Andrew K Lee
- Department of Pharmacology and Cancer Biology, Duke University Graduate School, Durham, North Carolina
| | | | | | | | | | - Chuan-Yuan Li
- Department of Pharmacology and Cancer Biology, Duke University Graduate School, Durham, North Carolina.,Department of Dermatology.,Department of Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina
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Verma A, Mathur R, Farooque A, Kaul V, Gupta S, Dwarakanath BS. T-Regulatory Cells In Tumor Progression And Therapy. Cancer Manag Res 2019; 11:10731-10747. [PMID: 31920383 PMCID: PMC6935360 DOI: 10.2147/cmar.s228887] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/06/2019] [Indexed: 12/24/2022] Open
Abstract
Regulatory T cells (Tregs) are important members of the immune system regulating the host responses to infection and neoplasms. Tregs prevent autoimmune disorders by protecting the host-cells from an immune response, related to the peripheral tolerance. However, tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response. Thus, Tregs are a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. This has prompted the development of novel adjuvant therapies that obviate their negative effects thereby enhancing the therapeutic efficacy. Our earlier studies have shown the efficacy of the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) by reducing the induced Tregs pool and enhance immune stimulation as well as local tumor control. These findings have suggested its potential for enhancing the efficacy of immunotherapy, besides radiotherapy and chemotherapy. This review provides a brief account of the current status of Tregs as a component of the immune-biology of tumors and various preclinical and clinical strategies pursued to obviate the limitations imposed by them in achieving therapeutic efficacy.
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Affiliation(s)
- Amit Verma
- Armed Forces Radiobiology Research Institute, Uniformed Services University, Bethesda, MD, USA
| | - Rohit Mathur
- Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Vandana Kaul
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, USA
| | - Seema Gupta
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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Hashemi V, Maleki LA, Esmaily M, Masjedi A, Ghalamfarsa G, Namdar A, Yousefi M, Yousefi B, Jadidi-Niaragh F. Regulatory T cells in breast cancer as a potent anti-cancer therapeutic target. Int Immunopharmacol 2019; 78:106087. [PMID: 31841758 DOI: 10.1016/j.intimp.2019.106087] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/23/2019] [Accepted: 11/25/2019] [Indexed: 02/08/2023]
Abstract
Despite marked advances in treatment approaches, breast cancer is still going to be more prevalent, worldwide. High levels of regulatory T (Treg) cells have repeatedly been demonstrated in circulation, lymph nodes, and tumor samples from patients with various cancer types. The transcription factor Forkhead box protein 3 (Foxp3)-expressing Treg cells have the high suppressive potential of the immune system and are fundamental in preserving immune homeostasis and self-tolerance. However, they enhance tumor development by curbing efficient anti-tumor immune mechanisms in malignancies. Moreover, the accumulation of Treg cells in breast tumors is related to the short overall survival of patients. Treg cell frequency has been applied as an independent predicting factor to diagnose patients with a high risk of relapse. Pulling out all populations of Treg cells to promote the efficacy of anticancer treatment methods may potentially lead to hazardous autoimmune disorders. Thus, realizing the exact structure of tumor-infiltrating Treg cells is pivotal to efficiently target Treg cells in tumors. There are exclusive and non-exclusive approaches to lower down and degrade the number/function of Treg cells. These approaches can include inhibiting tumoral migration, depletion, interference with function, and utilizing T cell plasticity. This review article attempts to clarify the implications concerning the involvement of Treg cells in breast cancer progression and discuss the current approaches in the treatment of this cancer via modulation of Treg cells function.
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Affiliation(s)
- Vida Hashemi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Basic Science, Faculty of Medicine, Maragheh University of Medical Sciences, Maragheh, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Maryam Esmaily
- Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Masjedi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Afshin Namdar
- Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Canada
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Immunology Research Center, 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 Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Singh S, Pandey S, Chawla AS, Bhatt AN, Roy BG, Saluja D, Dwarakanath BS. Dietary 2-deoxy-D-glucose impairs tumour growth and metastasis by inhibiting angiogenesis. Eur J Cancer 2019; 123:11-24. [PMID: 31670076 DOI: 10.1016/j.ejca.2019.09.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 09/09/2019] [Indexed: 01/05/2023]
Abstract
Accumulating evidence suggests the antiangiogenic potential of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) among the anticancerous properties of this drug. In the present studies, we investigated the antiangiogenic effects of dietary 2-DG on tumour (Lewis lung carcinoma [LLC]) as well as ionising radiation-induced angiogenesis in mouse models. Dietary 2-DG reduced the serum vascular endothelial growth factor levels (∼40%) in LLC-bearing mice along with a significant inhibition of tumour growth and metastases. In vivo Matrigel plug assays showed significant decrease in vascularisation, Fluorescein isothiocyanate (FITC)-dextran fluorescence and factor VIII-positive cells in the plugs from 2-DG-fed mice, supporting the notion that dietary 2-DG significantly suppresses the tumour-associated and radiation-induced angiogenesis. 2-DG inhibited the glucose usage and lactate production as well as ATP levels of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner, accompanied by growth inhibition and loss of viability in vitro. Furthermore, 2-DG inhibited the capillary-like tube formation in Matrigel as well as migration and transwell invasion by HUVECs, which are functional indicators of the process of angiogenesis. These results suggest that dietary 2-DG inhibits processes related to angiogenesis, which can impair the growth and metastasis of tumours.
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Affiliation(s)
- Saurabh Singh
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India; Medical Biotechnology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India; Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Sanjay Pandey
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India; Medical Biotechnology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India; Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Amanpreet Singh Chawla
- Medical Biotechnology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Anant Narayan Bhatt
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Bal Gangadhar Roy
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Daman Saluja
- Medical Biotechnology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Bilikere S Dwarakanath
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India; Shanghai Proton and Heavy Ion Center, Shanghai, China.
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Chen C, Ye Y, Wang R, Zhang Y, Wu C, Debnath SC, Ma Z, Wang J, Wu M. Streptomyces nigra sp. nov. Is a Novel Actinobacterium Isolated From Mangrove Soil and Exerts a Potent Antitumor Activity in Vitro. Front Microbiol 2018; 9:1587. [PMID: 30072967 PMCID: PMC6058180 DOI: 10.3389/fmicb.2018.01587] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 06/26/2018] [Indexed: 12/19/2022] Open
Abstract
A new bacterial strain, designated 452T, was isolated from the rhizosphere soil of the mangrove Avicennia marina in China. As determined, its cell wall peptidoglycan contained LL-diaminopimelic acid; MK-9(H8) and MK-9(H6) were the major isoprenoid quinones; and iso-C16:0 (31.3%), anteiso-C15:0 (16.9%), and iso-C15:0 (12.5%) were the major cellular fatty acids (>10.0%). Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain 452T formed a distinct lineage in the clade of the genus Streptomyces, and was closely related to S. coerulescens DSM 40146T (99.6% sequence identity), S. bellus DSM 40185T (99.5%), and S. coeruleorubidus DSM 41172T (99.3%). The DNA-DNA relatedness between strain 452T and these type strains ranged between 29.3 and 42.3%. Based on the phenotypic, chemotaxonomic, and phylogenetic features, the strain 452T is considered to represent a novel species of the genus Streptomyces, for which the name Streptomyces nigra sp. nov. is proposed. The type strain is 452T (=KCTC 39960T = MCCC 1K03346T). Further, strain 452T extracts exhibited a pronounced antitumor activity against human cancer cell lines A549, HCT-116, and HepG2, but not against normal human colon cells CCD-18Co. Active substances in the fermentation broth of strain 452T were isolated by bioassay-guided analysis, and then purified using a macroporous resin, silica gel, sephadex LX-20 column, and semi-preparative high-performance liquid chromatography (HPLC). Eight proline-containing diketopiperazines, namely, cyclo(Pro-Ala), cyclo(Pro-Gly), cyclo(Pro-Phe), cyclo(Pro-Met), cyclo(Pro-Val), cyclo(Pro-Leu), cyclo(Pro-Tyr), and cyclo(L-Leu-trans-4-hydroxy-L-Pro), were identified by electrospray ionization mass spectrometry (MS) and nuclear magnetic resonance (NMR). The compounds displayed different levels of cytotoxicity. The highest cytotoxicity was exhibited by cyclo(Pro-Ala) and cyclo(Pro-Met) against A549 cells, and cyclo(Phe-Pro) and cyclo(Pro-Ala) against HCT-116 cells, with average IC50 values equal to 18.5, 27.3, 32.3, and 47.6 μg/mL, respectively. The diversity of diketopiperazines and other chemicals produced by 452T was further investigated using gas chromatography (GC)-MS and liquid chromatography (LC)-MS. The analysis revealed 16 types of metabolites with antitumor activity and 16 other types of diketopiperazines. Hence, extracts of the newly identified strain may be used a starting material for the development of antitumor agents.
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Affiliation(s)
- Can Chen
- Laboratory of Marine Microbial Resources Utilization, Ocean College, Institute of Marine Biology, Zhejiang University, Hangzhou, China
| | - Yanghui Ye
- Laboratory of Marine Microbial Resources Utilization, Ocean College, Institute of Marine Biology, Zhejiang University, Hangzhou, China
| | - Ruijun Wang
- Laboratory of Marine Microbial Resources Utilization, Ocean College, Institute of Marine Biology, Zhejiang University, Hangzhou, China
| | - Yinglao Zhang
- Biomedical Research Program, School of Life Sciences, Anhui Agricultural University, Hefei, China
| | - Chen Wu
- Institute of Hydraulic and Marine Engineering, School of Hydraulic and Environmental Engineering, Zhejiang University of Water Resources and Electric Power, Hangzhou, China
| | - Sanjit C Debnath
- Laboratory of Marine Microbial Resources Utilization, Ocean College, Institute of Marine Biology, Zhejiang University, Hangzhou, China
| | - Zhongjun Ma
- Laboratory of Marine Microbial Resources Utilization, Ocean College, Institute of Marine Biology, Zhejiang University, Hangzhou, China
| | - Jidong Wang
- Department of New Drug Screening, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, China
| | - Min Wu
- Laboratory of Marine Microbial Resources Utilization, Ocean College, Institute of Marine Biology, Zhejiang University, Hangzhou, China
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17
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Dwarakanath BS, Farooque A, Gupta S. Targeting regulatory T cells for improving cancer therapy: Challenges and prospects. Cancer Rep (Hoboken) 2018; 1:e21105. [PMID: 32729245 DOI: 10.1002/cnr2.1105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/22/2018] [Accepted: 04/07/2018] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Regulatory T cells (Tregs) play a central role in immune responses to infectious agents and tumors. Paradoxically, Tregs protect self-cells from the immune response as a part of peripheral tolerance and prevents autoimmune disorders, whereas during the process of carcinogenesis, they are exploited by tumor cells for protection against antitumor immune responses. Therefore, Tregs are often considered as a major obstacle in anticancer therapy. The objective of this review is to provide a current understanding on Tregs as a potential cellular target for achieving therapeutic gain and discuss various approaches that are implicated at preclinical and clinical scenario. RECENT FINDINGS Several approaches like immunotherapy and adjuvant chemotherapy, which reduce Tregs population, have been found to be useful in improving local tumor control. Our recent observations with the glycolytic inhibitor, 2-deoxy-D-glucose, established as an adjuvant in radiotherapy and chemotherapy of tumors also show that potential of 2-deoxy-D-glucose to improve local tumor control is linked with its ability to reduce the Tregs pool. CONCLUSIONS Several published studies and emerging evidences indicate that suppression of Treg numbers, infiltration into the tumors, and function can improve the cancer therapy by enhancing the antitumor immunity.
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Affiliation(s)
| | | | - Seema Gupta
- Department of Oncology, Georgetown University, Washington, DC, USA
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18
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Shi X, Shiao SL. The role of macrophage phenotype in regulating the response to radiation therapy. Transl Res 2018; 191:64-80. [PMID: 29175267 PMCID: PMC6018060 DOI: 10.1016/j.trsl.2017.11.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 10/23/2017] [Accepted: 11/11/2017] [Indexed: 12/14/2022]
Abstract
Increasing experimental and clinical evidence has revealed a critical role for myeloid cells in the development and progression of cancer. The ability of monocytes and macrophages to regulate inflammation allows them to manipulate the tumor microenvironment to support the growth and development of malignant cells. Recent studies have shown that macrophages can exist in several functional states depending on the microenvironment they encounter in the tissue. These functional phenotypes influence not only the genesis and propagation of tumors, but also the efficacy of cancer therapies, particularly radiation. Early classification of the macrophage phenotypes, or "polarization states," identified 2 major states, M1 and M2, that have cytotoxic and wound repair capacity, respectively. In the context of tumors, classically activated or M1 macrophages driven by interferon-gamma support antitumor immunity while alternatively activated or M2 macrophages generated in part from interleukin-4 exposure hinder antitumor immunity by suppressing cytotoxic responses against a tumor. In this review, we discuss the role that the functional phenotype of a macrophage population plays in tumor development. We will then focus specifically on how macrophages and myeloid cells regulate the tumor response to radiation therapy.
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Affiliation(s)
- Xiaoshan Shi
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Stephen L Shiao
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA.
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Chen Z, Liu M, Li L, Chen L. Involvement of the Warburg effect in non-tumor diseases processes. J Cell Physiol 2017; 233:2839-2849. [PMID: 28488732 DOI: 10.1002/jcp.25998] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 05/08/2017] [Indexed: 12/16/2022]
Abstract
Warburg effect, as an energy shift from mitochondrial oxidative phosphorylation to aerobic glycolysis, is extensively found in various cancers. Interestingly, increasing researchers show that Warburg effect plays a crucial role in non-tumor diseases. For instance, inhibition of Warburg effect can alleviate pulmonary vascular remodeling in the process of pulmonary hypertension (PH). Interference of Warburg effect improves mitochondrial function and cardiac function in the process of cardiac hypertrophy and heart failure. Additionally, the Warburg effect induces vascular smooth muscle cell proliferation and contributes to atherosclerosis. Warburg effect may also involve in axonal damage and neuronal death, which are related with multiple sclerosis. Furthermore, Warburg effect significantly promotes cell proliferation and cyst expansion in polycystic kidney disease (PKD). Besides, Warburg effect relieves amyloid β-mediated cell death in Alzheimer's disease. And Warburg effect also improves the mycobacterium tuberculosis infection. Finally, we also introduce some glycolytic agonists. This review focuses on the newest researches about the role of Warburg effect in non-tumor diseases, including PH, tuberculosis, idiopathic pulmonary fibrosis (IPF), failing heart, cardiac hypertrophy, atherosclerosis, Alzheimer's diseases, multiple sclerosis, and PKD. Obviously, Warburg effect may be a potential therapeutic target for those non-tumor diseases.
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Affiliation(s)
- Zhe Chen
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Meiqing Liu
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Lanfang Li
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
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20
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Gupta S, Roy A, Dwarakanath BS. Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy. Front Oncol 2017; 7:68. [PMID: 28447025 PMCID: PMC5388702 DOI: 10.3389/fonc.2017.00068] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 03/24/2017] [Indexed: 12/31/2022] Open
Abstract
The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system, and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions. This metabolic reprogramming also plays a significant role in suppressing the immune attack on the tumor cells and in resistance to therapies. Thus, the metabolic cooperation and competition among the different TME components besides the inherent alterations in the tumor cells arising out of genetic as well as epigenetic changes supports growth, metastasis, and therapeutic resistance. This review focuses on the metabolic remodeling achieved through an active cooperation and competition among the three principal components of the TME—the tumor cells, the T cells, and the cancer-associated fibroblasts while discussing about the current strategies that target metabolism of TME components. Further, we will also consider the probable therapeutic opportunities targeting the various metabolic pathways as well as the signaling molecules/transcription factors regulating them for the development of novel treatment strategies for cancer.
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Affiliation(s)
- Seema Gupta
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Amrita Roy
- School of Life Sciences, B. S. Abdur Rahman Crescent University, Chennai, India
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21
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Arora A, Singh S, Bhatt AN, Pandey S, Sandhir R, Dwarakanath BS. Interplay Between Metabolism and Oncogenic Process: Role of microRNAs. TRANSLATIONAL ONCOGENOMICS 2015; 7:11-27. [PMID: 26740741 PMCID: PMC4696840 DOI: 10.4137/tog.s29652] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/11/2015] [Accepted: 11/18/2015] [Indexed: 12/17/2022]
Abstract
Cancer is a complex disease that arises from the alterations in the composition and regulation of several genes leading to the disturbances in signaling pathways, resulting in the dysregulation of cell proliferation and death as well as the ability of transformed cells to invade the host tissue and metastasize. It is increasingly becoming clear that metabolic reprograming plays a critical role in tumorigenesis and metastasis. Therefore, targeting this phenotype is considered as a promising approach for the development of therapeutics and adjuvants. The process of metabolic reprograming is linked to the activation of oncogenes and/or suppression of tumor suppressor genes, which are further regulated by microRNAs (miRNAs) that play important roles in the interplay between oncogenic process and metabolic reprograming. Looking at the advances made in the recent past, it appears that the translation of knowledge from research in the areas of metabolism, miRNA, and therapeutic response will lead to paradigm shift in the management of this disease.
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Affiliation(s)
- Aastha Arora
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.; Department of Biochemistry, Panjab University, Chandigarh, India
| | - Saurabh Singh
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Anant Narayan Bhatt
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Sanjay Pandey
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.; Dr B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Rajat Sandhir
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Bilikere S Dwarakanath
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.; Sri Ramachandra University, Chennai, India
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Farooque A, Afrin F, Adhikari JS, Dwarakanath BSR. Polarization of macrophages towards M1 phenotype by a combination of 2-deoxy-d-glucose and radiation: Implications for tumor therapy. Immunobiology 2015; 221:269-81. [PMID: 26597503 DOI: 10.1016/j.imbio.2015.10.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 10/08/2015] [Accepted: 10/26/2015] [Indexed: 12/18/2022]
Abstract
2-Deoxy-d-glucose (2-DG) has been found to enhance the cytotoxicity of ionizing radiation and chemotherapeutic drugs in several tumor cell lines in vitro. Systemic administration of 2-DG together with localized irradiation of the tumor leads to tumor regression and cure (disease free survival), which correlate with the differential levels of anti-tumor immunity observed in Ehrlich ascites tumor (EAT) bearing mice. Macrophages being a major player of the innate immune system, we investigated the activation status of splenic macrophages during radio-sensitization of EAT in mice as well as in peritoneal macrophages ex vivo and macrophagic cell line (Raw 264.7) in vitro. Results suggest that under in vivo conditions, the combined treatment (2-DG+radiation) restores the M1 phenotype in spleen that correlated with the tumor response. However, 2-DG neither induced significant cytotoxicity nor enhanced radiation-induced cell death in peritoneal macrophages and the macrophage cell line (Raw 264.7). Further, increased arborization and enhanced functional status (expression of MHC class II, CD80, CD86 and phagocytosis) were observed after the combined treatment. Besides this activation, the combined treatment also skewed the macrophages towards M1 phenotype as evidenced by the enhanced secretion of IL-12, IL-2, TNF-α and IFN-γ. These observations suggest that 2-DG not only preserves the survival of normal macrophages during irradiation, but also activates macrophages by polarizing towards M1 phenotype, which is known to be tumoricidal in nature. This study for the first time sheds light on a potential antitumor immune activation by 2-DG involving macrophagic stimulation during in vivo radio-sensitization of tumors, besides the other known antitumor effects of this glucose analogue.
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Affiliation(s)
- Abdullah Farooque
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Marg, Delhi 110054, India
| | - Farhat Afrin
- Department of Biotechnology, Jamia Hamdard (Hamdard University), New Delhi 110062, India
| | - Jawahar Singh Adhikari
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Marg, Delhi 110054, India
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Lee M, Yoon JH. Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. World J Biol Chem 2015; 6:148-61. [PMID: 26322173 PMCID: PMC4549759 DOI: 10.4331/wjbc.v6.i3.148] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 05/26/2015] [Accepted: 07/21/2015] [Indexed: 02/05/2023] Open
Abstract
Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
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24
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Singh S, Pandey S, Bhatt AN, Chaudhary R, Bhuria V, Kalra N, Soni R, Roy BG, Saluja D, Dwarakanath BS. Chronic Dietary Administration of the Glycolytic Inhibitor 2-Deoxy-D-Glucose (2-DG) Inhibits the Growth of Implanted Ehrlich's Ascites Tumor in Mice. PLoS One 2015; 10:e0132089. [PMID: 26135741 PMCID: PMC4489743 DOI: 10.1371/journal.pone.0132089] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 06/10/2015] [Indexed: 11/19/2022] Open
Abstract
Background Dietary energy restriction (DER) has been well established as a potent anticancer strategy. Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake. Glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has recently been shown to possess potential as an energy restriction mimetic agent (ERMA). In the present study we evaluated the effect of dietary 2-DG administration on a mouse tumor model, with a focus on several potential mechanisms that may account for the inhibition of tumorigenesis. Methodology/Principal Findings Swiss albino strain ‘A’ mice were administered with 0.2% and 0.4% w/v 2-DG in drinking water for 3 months prior to tumor implantation (Ehrlich’s ascites carcinoma; EAC) and continued till the termination of the study with no adverse effects on general physiology and animal growth. Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival. We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice. Also, reduced levels of certain key players of metabolic pathways such as phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and hypoxia inducible factor-1 alpha (HIF-1α) were also noted in tumors of 2-DG fed mice. Further, decrease in CD4+/CD8+ ratio and T-regulatory cells observed in 2-DG fed mice suggested enhanced antitumor immunity and T cell effector function. Conclusion/Significance These results strongly suggest that dietary 2-DG administration in mice, at doses easily achievable in humans, suitably modulates several pleotrophic factors mimicking DER and inhibits tumorigenesis, emphasizing the use of ERMAs as a promising cancer preventive strategy.
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MESH Headings
- Animals
- Antimetabolites, Antineoplastic/administration & dosage
- Antimetabolites, Antineoplastic/blood
- Antimetabolites, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/therapeutic use
- Blood Glucose/analysis
- CD4-CD8 Ratio
- Caloric Restriction
- Carcinoma, Ehrlich Tumor/blood supply
- Carcinoma, Ehrlich Tumor/drug therapy
- Carcinoma, Ehrlich Tumor/immunology
- Cell Division/drug effects
- Deoxyglucose/administration & dosage
- Deoxyglucose/blood
- Deoxyglucose/pharmacology
- Deoxyglucose/therapeutic use
- Drug Screening Assays, Antitumor
- Female
- Glycolysis/drug effects
- Insulin/blood
- Matrix Metalloproteinase 9/analysis
- Mice
- Neoplasm Proteins/physiology
- Neovascularization, Pathologic/drug therapy
- Premedication
- Random Allocation
- Signal Transduction/drug effects
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- Tumor Burden/drug effects
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Affiliation(s)
- Saurabh Singh
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
- Medical Biotechnology Laboratory, Dr B.R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Sanjay Pandey
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
- Medical Biotechnology Laboratory, Dr B.R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Anant Narayan Bhatt
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
| | - Richa Chaudhary
- Medical Biotechnology Laboratory, Dr B.R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Vikas Bhuria
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
| | - Namita Kalra
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
| | - Ravi Soni
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
| | - Bal Gangadhar Roy
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
| | - Daman Saluja
- Medical Biotechnology Laboratory, Dr B.R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Bilikere S. Dwarakanath
- Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, Brig. SK Mazumdar Road, Delhi, India
- * E-mail:
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