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Yuan MJ, Huang HC, Shi HS, Hu XM, Zhao Z, Chen YQ, Fan WJ, Sun J, Liu GB. MicroRNA-122-5p is upregulated in diabetic foot ulcers and decelerates the transition from the inflammatory to the proliferative stage. World J Diabetes 2025; 16:100113. [DOI: 10.4239/wjd.v16.i4.100113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 12/17/2024] [Accepted: 01/16/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Shifting from the inflammatory to the proliferative phase represents a pivotal step during managing diabetic foot ulcers (DFUs); however, existing medical interventions remain insufficient. MicroRNAs (miRs) highlight notable capacity for accelerating the repair process of DFUs. Previous research has demonstrated which miR-122-5p regulates matrix metalloproteinases under diabetic conditions, thereby influencing extracellular matrix dynamics.
AIM To investigate the impact of miR-122-5p on the transition from the inflammatory to the proliferative stage in DFU.
METHODS Analysis for miR-122-5p expression in skin tissues from diabetic ulcer patients and mice was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). A diabetic wound healing model induced by streptozotocin was used, with mice receiving intradermal injections of adeno-associated virus -DJ encoding empty vector or miR-122. Skin tissues were retrieved at 3, 7, and 14 days after injury for gene expression analysis, histology, immunohistochemistry, and network studies. The study explored miR-122-5p’s role in macrophage-fibroblast interactions and its effect on transitioning from inflammation to proliferation in DFU healing.
RESULTS High-throughput sequencing revealed miR-122-5p as crucial for DFU healing. qRT-PCR showed significant upregulation of miR-122-5p within diabetic skin among DFU individuals and mice. Western blot, along with immunohistochemical and enzyme-linked immunosorbent assay, demonstrating the upregulation of inflammatory mediators (hypoxia inducible factor-1α, matrix metalloproteinase 9, tumor necrosis factor-α) and reduced fibrosis markers (fibronectin 1, α-smooth muscle actin) by targeting vascular endothelial growth factor. Fluorescence in situ hybridization indicated its expression localized to epidermal keratinocytes and fibroblasts in diabetic mice. Immunofluorescence revealed enhanced increased presence of M1 macrophages and reduced M2 polarization, highlighting its role in inflammation. MiR-122-5p elevated inflammatory cytokine levels while suppressing fibrotic activity from fibroblasts exposed to macrophage-derived media, highlighting its pivotal role in regulating DFU healing.
CONCLUSION MiR-122-5p impedes cutaneous healing of diabetic mice via enhancing inflammation and inhibiting fibrosis, offering insights into miR roles in human skin wound repair.
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Affiliation(s)
- Mei-Jie Yuan
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - He-Chen Huang
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong-Shuo Shi
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiao-Ming Hu
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhuo Zhao
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yu-Qi Chen
- Department of Pathology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Jing Fan
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jian Sun
- Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guo-Bin Liu
- Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Chang DF, Li S, Court Pinto K, Nguyen TKC, Shah VV, Morales E, Carrier J, Ludlow AT, Brannan KW, Spiegel AJ, Davis O, Godin B, Mojiri A, Cooke JP. Telomerase mRNA Reduces Radiation-induced DNA Damage of human skin. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.01.636031. [PMID: 39975037 PMCID: PMC11838481 DOI: 10.1101/2025.02.01.636031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Over four million people undergo radiation therapy annually in the United States. Among these, more than 90% experience varying degrees of radiation-induced skin injury. Despite the enormity of the problem, there is currently no FDA-approved agent to prevent or treat skin damage caused by ionizing radiation. In the current study, ionizing radiation induced dosed-ependent genomic and mitochondrial DNA damage, leading to apoptosis in primary cutaneous cells. Prior treatment with mRNA encoding telomerase reverse transcriptase (TERT) substantially reduced radiation-induced DNA damage in human primary skin cells and tissues. Mechanistically, TERT mRNA pretreatment enhances DNA repair, reduces mitochondrial ROS, and decreases apoptosis without extending telomere length during the experimental period, suggesting a non-canonical function of TERT to accelerate the cellular recovery from radiation. These findings highlight a potential therapeutic approach for preventing radiation-induced skin injury.
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Affiliation(s)
- David F. Chang
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - Shuang Li
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - Karem Court Pinto
- Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, TX
| | - Thi Kim Cuc Nguyen
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - Vrutant V. Shah
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - Elisa Morales
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - Jack Carrier
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - Andrew T. Ludlow
- Department of Movement Science, University of Michigan, Ann Arbor, MI
| | | | | | - Olmsted Davis
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - Biana Godin
- Department of Obstetrics and Gynecology, Houston Methodist Hospital, Houston, TX
| | - Anahita Mojiri
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
| | - John P. Cooke
- Department of Cardiovascular Sciences, Houston Methodist Hospital, Houston, TX
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DiCarlo AL, Cassatt DR, Rios CI, Satyamitra MM, Zhang Y, Golden TG, Taliaferro LP. Making connections: the scientific impact and mentoring legacy of Dr. John E. Moulder. Int J Radiat Biol 2023:1-7. [PMID: 36763099 DOI: 10.1080/09553002.2023.2176563] [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: 02/11/2023]
Abstract
PURPOSE The intent of this mini review is to pay homage to Dr. John E. Moulder's long and successful career in radiation science with the Medical College of Wisconsin. This effort will be done from the perspective of his history of U.S. Government funding for research into the biological pathways involved in radiation-induced normal tissue injuries, especially damage to the kidneys and heart, and pharmacological interventions. In addition, the impact of his steady guidance and leadership in the mentoring of junior scientists, and the development of meaningful collaborations with other researchers will be highlighted. CONCLUSION Dr. John E. Moulder's contributions to the field of radiation research, through his strong character and reputation, his consistent and dedicated commitment to his colleagues and students, and his significant scientific advances, have been critical to moving the science forward, and will not be forgotten by those who knew him personally or through publications documenting his important work.
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Affiliation(s)
- Andrea L DiCarlo
- Radiation and Nuclear Countermeasures Program; Division of Allergy, Immunology, and Transplantation; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - David R Cassatt
- Radiation and Nuclear Countermeasures Program; Division of Allergy, Immunology, and Transplantation; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Carmen I Rios
- Radiation and Nuclear Countermeasures Program; Division of Allergy, Immunology, and Transplantation; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Merriline M Satyamitra
- Radiation and Nuclear Countermeasures Program; Division of Allergy, Immunology, and Transplantation; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Yuji Zhang
- Department of Epidemiology and Public Health, Marlene and Stewart Greenbaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Trevor G Golden
- Radiation and Nuclear Countermeasures Program; Division of Allergy, Immunology, and Transplantation; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Lanyn P Taliaferro
- Radiation and Nuclear Countermeasures Program; Division of Allergy, Immunology, and Transplantation; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
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Kim JH, Brown SL, Gordon MN. Radiation-induced senescence: therapeutic opportunities. Radiat Oncol 2023; 18:10. [PMID: 36639774 PMCID: PMC9837958 DOI: 10.1186/s13014-022-02184-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 12/19/2022] [Indexed: 01/15/2023] Open
Abstract
The limitation of cancer radiotherapy does not derive from an inability to ablate tumor, but rather to do so without excessively damaging critical tissues and organs and adversely affecting patient's quality of life. Although cellular senescence is a normal consequence of aging, there is increasing evidence showing that the radiation-induced senescence in both tumor and adjacent normal tissues contributes to tumor recurrence, metastasis, and resistance to therapy, while chronic senescent cells in the normal tissue and organ are a source of many late damaging effects. In this review, we discuss how to identify cellular senescence using various bio-markers and the role of the so-called senescence-associated secretory phenotype characteristics on the pathogenesis of the radiation-induced late effects. We also discuss therapeutic options to eliminate cellular senescence using either senolytics and/or senostatics. Finally, a discussion of cellular reprogramming is presented, another promising avenue to improve the therapeutic gain of radiotherapy.
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Affiliation(s)
- Jae Ho Kim
- grid.239864.20000 0000 8523 7701Radiobiology Research Laboratories, Department of Radiation Oncology, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202 USA
| | - Stephen L. Brown
- grid.239864.20000 0000 8523 7701Radiobiology Research Laboratories, Department of Radiation Oncology, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202 USA
| | - Marcia N. Gordon
- grid.17088.360000 0001 2150 1785Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI 49503 USA
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Mechanism and Protection of Radiotherapy Induced Sensorineural Hearing Loss for Head and Neck Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2021:3548706. [PMID: 34970625 PMCID: PMC8714384 DOI: 10.1155/2021/3548706] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/18/2021] [Accepted: 12/08/2021] [Indexed: 12/15/2022]
Abstract
Purpose Radiotherapy-induced sensorineural hearing loss (RISNHL) is a common adverse effect in patients with head and neck cancer. Given that there are few studies on the pathogenesis of RISNHL at present, we summarized the possible pathogenesis of RISNHL and possible protective measures found at present by referring to relevant literatures. Methods We performed a comprehensive literature search in the PubMed database, using keywords “sensorineural hearing loss,” “radiotherapy,” and “cancer,” among others. The literature was examined for the possible mechanism and preventive measures of sensorineural hearing loss induced by radiotherapy. Results We found that the incidence of RISNHL was closely related to the damage directly caused by ionizing radiation and the radiation-induced bystander effect. It also depends on the dose of radiation and the timing of chemotherapy. Studies confirmed that RISNHL is mainly involved in post-RT inflammatory response and changes in reactive oxygen species, mitogen-activated protein kinase, and p53 signaling pathways, leading to specific manners of cell death. We expect to reduce the incidence of hearing loss through advanced radiotherapy techniques, dose limitation of organs at risk, application of cell signaling inhibitors, use of antioxidants, induction of cochlear hair cell regeneration, and cochlear implantation. Conclusion RISNHL is associated with radiation damage to DNA, oxidative stress, and inflammation of cochlear cells, stria vascularis endothelial cells, vascular endothelial cells, spiral ganglion neurons, and other supporting cells. At present, the occurrence mechanism of RISNHL has not been clearly illustrated, and further studies are needed to better understand the underlying mechanism, which is crucial to promote the formulation of better strategies and prevent the occurrence of RISNHL.
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Zhang J, Zhu Y, Zhang Y, Lin W, Ke J, Liu J, Zhang L, Liu J. A balanced charged hydrogel with anti-biofouling and antioxidant properties for treatment of irradiation-induced skin injury. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 131:112538. [PMID: 34857314 DOI: 10.1016/j.msec.2021.112538] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 10/22/2021] [Accepted: 11/03/2021] [Indexed: 01/18/2023]
Abstract
Skin injury caused by large doses of ionizing radiation is the common and severe side effect of radiotherapy. However, its therapeutic efficacy is always hindered by early reactive oxygen species generation, repetitive inflammatory microenvironment and bacterial infection risk. Herein, we report an anti-biofouling hydrogel with anti-inflammation and anti-oxidative properties for the treatment of irradiation-induced skin injury. The anti-biofouling hydrogel can be achieved by balancing oppositely charged alginate, hyaluronic acid (HA) and polylysine (PLL) at the optimal ratio, which effectively resist protein and bacterial adhesion, and evades immune response. Moreover, curcumin and epigallocatechin gallate (EGCG) can be facially encapsulated and substantially released from the hydrogel. Results showed that the resulting AHP-Cur/EGCG hydrogel can significantly weaken the development of skin injury and accelerate its healing process by alleviating inflammation, scavenging ROS and promoting angiogenesis. Therefore, the findings presented in this work provide an effective strategy for clinical management and treatment of ionizing radiation-induced skin injury.
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Affiliation(s)
- Jiamin Zhang
- Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Yingnan Zhu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Yumin Zhang
- Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Wenjing Lin
- Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Jia Ke
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (MOE), Tianjin University, Tianjin 300350, China
| | - Jianfeng Liu
- Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China
| | - Lei Zhang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (MOE), Tianjin University, Tianjin 300350, China.
| | - Jinjian Liu
- Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China.
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Sishc BJ, Ding L, Nam TK, Heer CD, Rodman SN, Schoenfeld JD, Fath MA, Saha D, Pulliam CF, Langen B, Beardsley RA, Riley DP, Keene JL, Spitz DR, Story MD. Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide. Sci Transl Med 2021; 13:eabb3768. [PMID: 33980575 PMCID: PMC8314936 DOI: 10.1126/scitranslmed.abb3768] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 04/20/2021] [Indexed: 12/11/2022]
Abstract
Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice were given AVA once before tumor irradiation and further increased when AVA was given before and for 4 days after radiation, supporting a role for oxidative metabolism. This synergy was abrogated by conditional overexpression of catalase in the tumors. In addition, in vitro NSCLC and mammary adenocarcinoma models showed that AVA increased intracellular hydrogen peroxide concentrations and buthionine sulfoximine- and auranofin-induced inhibition of glutathione- and thioredoxin-dependent hydrogen peroxide metabolism selectively enhanced AVA-induced killing of cancer cells compared to normal cells. Gene expression in irradiated tumors treated with AVA suggested that increased inflammatory, TNFα, and apoptosis signaling also contributed to treatment synergy. These results support the hypothesis that AVA, although reducing radiotherapy damage to normal tissues, acts synergistically only with high dose per fraction radiation regimens analogous to stereotactic ablative body radiotherapy against tumors by a hydrogen peroxide-dependent mechanism. This tumoricidal synergy is now being tested in a phase I-II clinical trial in humans (NCT03340974).
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Affiliation(s)
- Brock J Sishc
- Division of Molecular Radiation Biology, Department of Radiation Oncology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lianghao Ding
- Division of Molecular Radiation Biology, Department of Radiation Oncology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Taek-Keun Nam
- Division of Molecular Radiation Biology, Department of Radiation Oncology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Collin D Heer
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Samuel N Rodman
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Joshua D Schoenfeld
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Melissa A Fath
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Debabrata Saha
- Division of Molecular Radiation Biology, Department of Radiation Oncology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Casey F Pulliam
- Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Britta Langen
- Division of Molecular Radiation Biology, Department of Radiation Oncology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Robert A Beardsley
- Galera Therapeutics Inc., 2 West Liberty Blvd., Suite 110, Malvern, PA 19355, USA
| | - Dennis P Riley
- Galera Therapeutics Inc., 2 West Liberty Blvd., Suite 110, Malvern, PA 19355, USA
| | - Jeffery L Keene
- Galera Therapeutics Inc., 2 West Liberty Blvd., Suite 110, Malvern, PA 19355, USA
| | - Douglas R Spitz
- Galera Therapeutics Inc., 2 West Liberty Blvd., Suite 110, Malvern, PA 19355, USA.
| | - Michael D Story
- Division of Molecular Radiation Biology, Department of Radiation Oncology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Sonis ST. Superoxide Dismutase as an Intervention for Radiation Therapy-Associated Toxicities: Review and Profile of Avasopasem Manganese as a Treatment Option for Radiation-Induced Mucositis. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:1021-1029. [PMID: 33716500 PMCID: PMC7944116 DOI: 10.2147/dddt.s267400] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/19/2021] [Indexed: 11/23/2022]
Abstract
Toxicities associated with radiation therapy are common, symptomatically devastating, and costly. The best chance to effectively mitigate radiation-associated normal tissue side effects are interventions aimed at disrupting the biological cascade, which is the basis for toxicity development, while simultaneously not reducing the beneficial impact of radiation on tumor. Oxidative stress is a key initiator of radiation-associated normal tissue injury as physiologic antioxidant mechanisms are overwhelmed by the accumulation of effects produced by fractionated treatment regimens. And fundamental to this is the generation of superoxide, which is normally removed by superoxide dismutases (SODs). Attempts to supplement the activity of endogenous SOD to prevent radiation-induced normal tissue injury have included the administration of bovine-derived SOD and increasing SOD production using gene transfer, neither of which has resulted in a clinically acceptable therapy. A third approach has been to develop synthetic small molecule dismutase mimetics. This approach has led to the creation and development of avasopasem manganese, a unique and specific dismutase mimetic that, in clinical trials, has shown promising potential to reduce the incidence, severity and duration of severe oral mucositis amongst patients being treated with concomitant chemoradiation for cancers of the head and neck. Further, avasopasem and related analogues have demonstrated mechanism-related antitumor synergy in combination with high dose per fraction radiotherapy, an observation that is also being tested in clinical trials. An ongoing Phase 3 trial seeks to confirm avasopasem manganese as an effective intervention for severe oral mucositis associated with chemoradiation in head and neck cancer patients.
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Affiliation(s)
- Stephen T Sonis
- Primary Endpoint Solutions, Waltham, MA, 02451, USA.,Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, MA, 02215, USA
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Brand MD. Riding the tiger - physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix. Crit Rev Biochem Mol Biol 2020; 55:592-661. [PMID: 33148057 DOI: 10.1080/10409238.2020.1828258] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Elevated mitochondrial matrix superoxide and/or hydrogen peroxide concentrations drive a wide range of physiological responses and pathologies. Concentrations of superoxide and hydrogen peroxide in the mitochondrial matrix are set mainly by rates of production, the activities of superoxide dismutase-2 (SOD2) and peroxiredoxin-3 (PRDX3), and by diffusion of hydrogen peroxide to the cytosol. These considerations can be used to generate criteria for assessing whether changes in matrix superoxide or hydrogen peroxide are both necessary and sufficient to drive redox signaling and pathology: is a phenotype affected by suppressing superoxide and hydrogen peroxide production; by manipulating the levels of SOD2, PRDX3 or mitochondria-targeted catalase; and by adding mitochondria-targeted SOD/catalase mimetics or mitochondria-targeted antioxidants? Is the pathology associated with variants in SOD2 and PRDX3 genes? Filtering the large literature on mitochondrial redox signaling using these criteria highlights considerable evidence that mitochondrial superoxide and hydrogen peroxide drive physiological responses involved in cellular stress management, including apoptosis, autophagy, propagation of endoplasmic reticulum stress, cellular senescence, HIF1α signaling, and immune responses. They also affect cell proliferation, migration, differentiation, and the cell cycle. Filtering the huge literature on pathologies highlights strong experimental evidence that 30-40 pathologies may be driven by mitochondrial matrix superoxide or hydrogen peroxide. These can be grouped into overlapping and interacting categories: metabolic, cardiovascular, inflammatory, and neurological diseases; cancer; ischemia/reperfusion injury; aging and its diseases; external insults, and genetic diseases. Understanding the involvement of mitochondrial matrix superoxide and hydrogen peroxide concentrations in these diseases can facilitate the rational development of appropriate therapies.
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10
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Obrador E, Salvador R, Villaescusa JI, Soriano JM, Estrela JM, Montoro A. Radioprotection and Radiomitigation: From the Bench to Clinical Practice. Biomedicines 2020; 8:E461. [PMID: 33142986 PMCID: PMC7692399 DOI: 10.3390/biomedicines8110461] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023] Open
Abstract
The development of protective agents against harmful radiations has been a subject of investigation for decades. However, effective (ideal) radioprotectors and radiomitigators remain an unsolved problem. Because ionizing radiation-induced cellular damage is primarily attributed to free radicals, radical scavengers are promising as potential radioprotectors. Early development of such agents focused on thiol synthetic compounds, e.g., amifostine (2-(3-aminopropylamino) ethylsulfanylphosphonic acid), approved as a radioprotector by the Food and Drug Administration (FDA, USA) but for limited clinical indications and not for nonclinical uses. To date, no new chemical entity has been approved by the FDA as a radiation countermeasure for acute radiation syndrome (ARS). All FDA-approved radiation countermeasures (filgrastim, a recombinant DNA form of the naturally occurring granulocyte colony-stimulating factor, G-CSF; pegfilgrastim, a PEGylated form of the recombinant human G-CSF; sargramostim, a recombinant granulocyte macrophage colony-stimulating factor, GM-CSF) are classified as radiomitigators. No radioprotector that can be administered prior to exposure has been approved for ARS. This differentiates radioprotectors (reduce direct damage caused by radiation) and radiomitigators (minimize toxicity even after radiation has been delivered). Molecules under development with the aim of reaching clinical practice and other nonclinical applications are discussed. Assays to evaluate the biological effects of ionizing radiations are also analyzed.
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Affiliation(s)
- Elena Obrador
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Rosario Salvador
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Juan I. Villaescusa
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain;
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
| | - José M. Soriano
- Food & Health Lab, Institute of Materials Science, University of Valencia, 46980 Valencia, Spain;
- Joint Research Unit in Endocrinology, Nutrition and Clinical Dietetics, University of Valencia-Health Research Institute IISLaFe, 46026 Valencia, Spain
| | - José M. Estrela
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (E.O.); (R.S.); (J.M.E.)
| | - Alegría Montoro
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain;
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
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Wang Y, Tu W, Tang Y, Zhang S. Prevention and treatment for radiation-induced skin injury during radiotherapy. RADIATION MEDICINE AND PROTECTION 2020. [DOI: 10.1016/j.radmp.2020.02.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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12
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Khalifa J, François S, Rancoule C, Riccobono D, Magné N, Drouet M, Chargari C. Gene therapy and cell therapy for the management of radiation damages to healthy tissues: Rationale and early results. Cancer Radiother 2019; 23:449-465. [PMID: 31400956 DOI: 10.1016/j.canrad.2019.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/06/2019] [Indexed: 12/14/2022]
Abstract
Nowadays, ionizing radiations have numerous applications, especially in medicine for diagnosis and therapy. Pharmacological radioprotection aims at increasing detoxification of free radicals. Radiomitigation aims at improving survival and proliferation of damaged cells. Both strategies are essential research area, as non-contained radiation can lead to harmful effects. Some advances allowing the comprehension of normal tissue injury mechanisms, and the discovery of related predictive biomarkers, have led to developing several highly promising radioprotector or radiomitigator drugs. Next to these drugs, a growing interest does exist for biotherapy in this field, including gene therapy and cell therapy through mesenchymal stem cells. In this review article, we provide an overview of the management of radiation damages to healthy tissues via gene or cell therapy in the context of radiotherapy. The early management aims at preventing the occurrence of these damages before exposure or just after exposure. The late management offers promises in the reversion of constituted late damages following irradiation.
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Affiliation(s)
- J Khalifa
- Départment de radiothérapie, institut Claudius-Regaud, institut universitaire du cancer de Toulouse - Oncopole, 1, avenue Irène-Joliot-Curie, 31100 Toulouse, France.
| | - S François
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - C Rancoule
- Département de radiothérapie, institut de cancérologie de la Loire Lucien-Neuwirth, 108 bis, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; Laboratoire de radiobiologie cellulaire et moléculaire, UMR 5822, institut de physique nucléaire de Lyon (IPNL), 69622 Villeurbanne, France; UMR 5822, CNRS, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université Lyon 1, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université de Lyon, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France
| | - D Riccobono
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - N Magné
- Département de radiothérapie, institut de cancérologie de la Loire Lucien-Neuwirth, 108 bis, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; Laboratoire de radiobiologie cellulaire et moléculaire, UMR 5822, institut de physique nucléaire de Lyon (IPNL), 69622 Villeurbanne, France; UMR 5822, CNRS, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université Lyon 1, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université de Lyon, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France
| | - M Drouet
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - C Chargari
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France; Service de santé des armées, école du Val-de-Grâce, 74, boulevard de Port-Royal, 75005 Paris, France; Département de radiothérapie, Gustave-Roussy Cancer Campus, 114, rue Édouard-Vailant, 94805 Villejuif, France
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13
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Park SW, Choi J, Kim J, Jeong W, Kim JS, Jeong BK, Shin SC, Kim JH. Anthocyanins from black soybean seed coat prevent radiation-induced skin fibrosis by downregulating TGF-β and Smad3 expression. Arch Dermatol Res 2018; 310:401-412. [PMID: 29556751 DOI: 10.1007/s00403-018-1827-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 03/09/2018] [Accepted: 03/14/2018] [Indexed: 12/21/2022]
Abstract
The aim of this study was to evaluate the protective effects of anthocyanins from the black soybean seed coat against radiation injury in dermal fibroblasts and mouse skin. Dermal fibroblasts treated with 50 and 100 µg/mL anthocyanins were irradiated with single doses of 20 Gy. Cell viability, intracellular reactive oxygen species (ROS) production, and mRNA expression were measured. A total of 60 mice were used for an in vivo study. A dose of 100 µg/mL anthocyanins was administered daily for 5 days before or after radiation therapy. Following irradiation (45 Gy), mice were inspected for gross pathology twice per wk for 8 weeks. At 4 and 8 weeks post-irradiation, dorsal skin was harvested for histopathologic examination and protein isolation. In dermal fibroblasts, treatment with 50 and 100 µg/mL anthocyanins significantly reduced radiation-induced apoptosis at 72 h and intracellular reactive oxygen species generation at 48 h. Furthermore, 100 µg/mL anthocyanins markedly decreased Smad3 mRNA expression and increased Smad7 mRNA expression at 72 h post-irradiation. In mice, treatment with 100 µg/mL anthocyanins resulted in a significant reduction in the level of skin injury, epidermal thickness, and collagen deposition after irradiation. Treatment with 100 µg/mL anthocyanins significantly decreased the number of α-SMA-, TGF-β-, and Smad3-positive cells after irradiation. Our study demonstrated that black soybean anthocyanins inhibited radiation-induced fibrosis by downregulating TGF-β and Smad3 expression. Therefore, anthocyanins may be a safe and effective candidate for the prevention of radiation-induced skin fibrosis.
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Affiliation(s)
- Sang Woo Park
- Department of Plastic and Reconstructive Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea
| | - Jaehoon Choi
- Department of Plastic and Reconstructive Surgery, Keimyung University School of Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea.
| | - Junhyung Kim
- Department of Plastic and Reconstructive Surgery, Keimyung University School of Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Woohhyeok Jeong
- Department of Plastic and Reconstructive Surgery, Keimyung University School of Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Jun Sik Kim
- Department of Plastic and Reconstructive Surgery, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
| | - Bae Kwon Jeong
- Department of Radiation Oncology, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - Sung Chul Shin
- Department of Chemistry, Research Institute of Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Jin Hee Kim
- Department of Radiation Oncology, Keimyung University School of Medicine, Daegu, Republic of Korea
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14
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Bonetta R. Potential Therapeutic Applications of MnSODs and SOD-Mimetics. Chemistry 2017; 24:5032-5041. [DOI: 10.1002/chem.201704561] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Rosalin Bonetta
- Centre of Molecular Medicine and Biobanking; University of Malta; Msida MSD2080 Malta
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15
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Xue J, Yu C, Sheng W, Zhu W, Luo J, Zhang Q, Yang H, Cao H, Wang W, Zhou J, Wu J, Cao P, Chen M, Ding WQ, Cao J, Zhang S. The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade. J Invest Dermatol 2017; 137:2059-2068. [PMID: 28596000 DOI: 10.1016/j.jid.2017.05.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 05/07/2017] [Accepted: 05/16/2017] [Indexed: 12/27/2022]
Abstract
Radiation-induced skin injury is a common side effect of radiotherapy and can limit the duration and dose of radiotherapy. Most early work focused on elimination of reactive oxygen species (ROS) after radiation; however, less is known about the mechanisms underlying amplification of ROS and consequent skin injury by radiation. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for all nitric oxide synthases. Inadequate availability of BH4 leads to uncoupling of nitric oxide synthases and production of highly oxidative radicals. In this study, we demonstrated that radiation disrupted BH4, which resulted in nitric oxide synthases uncoupling and augmented radiation-induced ROS. Overexpression of GTP cyclohydrolase I (GCH1), the rate-limiting enzyme for BH4 synthesis, restored cellular BH4 levels and nitric oxide production and decreased radiation-induced ROS. GCH1 also protected skin cells and rat skins against radiation-induced damage. We found that GCH1 was regulated by NF-E2-related factor 2, a key mediator of the cellular antioxidant response. Importantly, we identified GCH1 as a key effector for NF-E2-related factor 2-mediated protection against radiation-induced skin injury by inhibiting ROS production. Taken together, the findings of this study illustrate the key role of the NF-E2-related factor 2/GCH1/BH4 axis during radiation-induced skin damage.
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Affiliation(s)
- Jiao Xue
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Chenxiao Yu
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Wenjiong Sheng
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Wei Zhu
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Judong Luo
- Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, China
| | - Qi Zhang
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Hongying Yang
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Han Cao
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China
| | - Wenjie Wang
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China
| | - Jundong Zhou
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China
| | - Jinchang Wu
- Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, China
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Ming Chen
- Zhejiang Key Laboratory of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| | - Jianping Cao
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China.
| | - Shuyu Zhang
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China; Zhejiang Key Laboratory of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
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16
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Kamran MZ, Ranjan A, Kaur N, Sur S, Tandon V. Radioprotective Agents: Strategies and Translational Advances. Med Res Rev 2016; 36:461-93. [PMID: 26807693 DOI: 10.1002/med.21386] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 12/15/2015] [Accepted: 01/01/2016] [Indexed: 01/08/2023]
Abstract
Radioprotectors are agents required to protect biological system exposed to radiation, either naturally or through radiation leakage, and they protect normal cells from radiation injury in cancer patients undergoing radiotherapy. It is imperative to study radioprotectors and their mechanism of action comprehensively, looking at their potential therapeutic applications. This review intimately chronicles the rich intellectual, pharmacological story of natural and synthetic radioprotectors. A continuous effort is going on by researchers to develop clinically promising radioprotective agents. In this article, for the first time we have discussed the impact of radioprotectors on different signaling pathways in cells, which will create a basis for scientific community working in this area to develop novel molecules with better therapeutic efficacy. The bright future of exceptionally noncytotoxic derivatives of bisbenzimidazoles is also described as radiomodulators. Amifostine, an effective radioprotectant, has been approved by the FDA for limited clinical use. However, due to its adverse side effects, it is not routinely used clinically. Recently, CBLB502 and several analog of a peptide are under clinical trial and showed high success against radiotherapy in cancer. This article reviews the different types of radioprotective agents with emphasis on the strategies for the development of novel radioprotectors for drug development. In addition, direction for future strategies relevant to the development of radioprotectors is also addressed.
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Affiliation(s)
- Mohammad Zahid Kamran
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Atul Ranjan
- Kansas University of Medical Center, Kansas City, KS, 66160
| | - Navrinder Kaur
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Souvik Sur
- Department of Chemistry, University of Delhi, Delhi, 110007, India
| | - Vibha Tandon
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.,Department of Chemistry, University of Delhi, Delhi, 110007, India
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17
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Kim JH, Jenrow KA, Brown SL. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials. Radiat Oncol J 2014; 32:103-15. [PMID: 25324981 PMCID: PMC4194292 DOI: 10.3857/roj.2014.32.3.103] [Citation(s) in RCA: 210] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 08/18/2014] [Indexed: 01/10/2023] Open
Abstract
To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.
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Affiliation(s)
- Jae Ho Kim
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA
| | - Kenneth A. Jenrow
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA
| | - Stephen L. Brown
- Department of Radiation Oncology, Henry Ford Health System, Detroit, MI, USA
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18
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Zhang S, Wang W, Gu Q, Xue J, Cao H, Tang Y, Xu X, Cao J, Zhou J, Wu J, Ding WQ. Protein and miRNA profiling of radiation-induced skin injury in rats: the protective role of peroxiredoxin-6 against ionizing radiation. Free Radic Biol Med 2014; 69:96-107. [PMID: 24447893 DOI: 10.1016/j.freeradbiomed.2014.01.019] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 01/08/2014] [Accepted: 01/13/2014] [Indexed: 01/29/2023]
Abstract
Radiation-induced skin injury is a serious concern during radiotherapy. However, the molecular mechanism underlying the pathogenesis of radiation-induced skin injury has not been extensively reported. Most biological functions are performed and regulated by proteins and noncoding RNAs, including microRNAs (miRNAs). The interplay between mRNA and miRNA has been implicated in disease initiation and progression. Technical advances in genomics and proteomics have enabled the exploration of the etiology of diseases and have the potential to broaden our understanding of the molecular pathogenesis of radiation-induced skin injury. In this study, we compared the protein and miRNA expression in rat skin irradiated with a 45-Gy electron beam with expression from adjacent normal tissues. We found 24 preferentially expressed proteins and 12 dysregulated miRNAs in irradiated skin. By analyzing the protein and miRNA profiles using bioinformatics tools, we identified a possible interaction between miR-214 and peroxiredoxin-6 (PRDX-6). Next, we investigated the expression of PRDX-6 and the consequences of its dysregulation. PRDX-6 is suppressed by radiation-inducible miR-214 and is involved in the pathogenesis of radiation-induced skin injury. Overexpression of PRDX-6 conferred radioresistance on cells, decreased cell apoptosis, and preserved mitochondrial integrity after radiation exposure. In addition, in vivo transfection with PRDX-6 reduced radiation-induced reactive oxygen species and the malondialdehyde concentration and ameliorated radiation-induced skin damage in rats. Our present findings illustrate the molecular changes during radiation-induced skin injury and the important role of PRDX-6 in ameliorating this damage in rats.
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Affiliation(s)
- Shuyu Zhang
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
| | - Wenjie Wang
- Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China
| | - Qing Gu
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Jiao Xue
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Han Cao
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Yiting Tang
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Xiaohui Xu
- Department of General Surgery, Second Affiliated Hospital, Soochow University, Suzhou 215004, China
| | - Jianping Cao
- School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
| | - Jundong Zhou
- Department of Radio-oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215001, China
| | - Jinchang Wu
- Department of Radio-oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215001, China
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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19
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Zhang S, Wang W, Peng Y, Gu Q, Luo J, Zhou J, Wu J, Hou Y, Cao J. Amelioration of radiation-induced skin injury by HIV-TAT-mediated protein transduction of RP-1 from Rana pleurade. Int J Med Sci 2014; 11:44-51. [PMID: 24396285 PMCID: PMC3880990 DOI: 10.7150/ijms.7463] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 12/11/2013] [Indexed: 11/20/2022] Open
Abstract
Radiation-induced reactive oxygen species (ROS) can damage DNA and most other biological macromolecules in skin and radiation-induced skin injury is a serious concern for radiation therapy. Skin possesses an extremely efficient antioxidant system, which is conferred by two systems: antioxidant enzymes and small molecules that can scavenge ROS by donating electrons. Amphibian skin is a multifunctional organ, which protects against dangers of various oxidative stresses. Recently, a small peptide called RP-1 was isolated from the skin secretions of Rana pleurade, which shows strong antioxidant activity. However, this RP-1 peptide is limited because its inability to across the cell membrane. Protein transduction domains (PTDs) have demonstrated high efficiency for facilitating the internalization of both homologous and heterogeneous proteins into cells. This study aims to elucidate the protective effects of a HIV-TAT (TAT) PTD-coupled RP-1 fusion protein (TAT-RP1) on radiation-induced skin injury in vitro and in vivo. The synthesized fusion TAT-RP1 peptide can be incorporated into human keratinocyte HaCaT cells in a dose- and time-dependent manner without cytotoxicity. We then evaluated the protective role of TAT-RP1 against ionizing radiation. TAT-RP1 supplementation increased anti-superoxide anion ability of HaCaT cells and decreased HaCaT cell radiosensitivity to irradiation. Moreover, TAT-RP1 was able to penetrate the skin of rats, entering epidermis as well as the dermis of the subcutaneous layer in skin tissue. Topical spread of TAT-RP1 promoted the amelioration of radiation-induced skin damage in rats. These results suggest that TAT-RP1 has potential as a protein therapy for radiation-induced skin injury.
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Affiliation(s)
- Shuyu Zhang
- 1. School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China
| | - Wenjie Wang
- 2. Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China
| | - Ying Peng
- 3. Jiangsu Institute of Nuclear Medicine and Key Laboratory of Nuclear Medicine, Ministry of Health, Wuxi 214063, China
| | - Qing Gu
- 1. School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China
| | - Judong Luo
- 1. School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China
| | - Jundong Zhou
- 4. Department of Radio-oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215001, China
| | - Jinchang Wu
- 4. Department of Radio-oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215001, China
| | - Yinglong Hou
- 5. Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, China
| | - Jianping Cao
- 1. School of Radiation Medicine and Protection and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China
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20
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Doctrow SR, Lopez A, Schock AM, Duncan NE, Jourdan MM, Olasz EB, Moulder JE, Fish BL, Mäder M, Lazar J, Lazarova Z. A synthetic superoxide dismutase/catalase mimetic EUK-207 mitigates radiation dermatitis and promotes wound healing in irradiated rat skin. J Invest Dermatol 2013; 133:1088-96. [PMID: 23190879 PMCID: PMC3594042 DOI: 10.1038/jid.2012.410] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In the event of a radionuclear attack or nuclear accident, the skin would be the first barrier exposed to radiation, though skin injury can progress over days to years following exposure. Chronic oxidative stress has been implicated as being a potential contributor to the progression of delayed radiation-induced injury to skin and other organs. To examine the causative role of oxidative stress in delayed radiation-induced skin injury, including impaired wound healing, we tested a synthetic superoxide dismutase (SOD)/catalase mimetic, EUK-207, in a rat model of combined skin irradiation and wound injury. Administered systemically, beginning 48 hours after irradiation, EUK-207 mitigated radiation dermatitis, suppressed indicators of tissue oxidative stress, and enhanced wound healing. Evaluation of gene expression in irradiated skin at 30 days after exposure revealed a significant upregulation of several key genes involved in detoxication of reactive oxygen and nitrogen species. This gene expression pattern was primarily reversed by EUK-207 therapy. These results demonstrate that oxidative stress has a critical role in the progression of radiation-induced skin injury, and that the injury can be mitigated by appropriate antioxidant compounds administered 48 hours after exposure.
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Affiliation(s)
- Susan R. Doctrow
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Argelia Lopez
- Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
| | - Ashley M. Schock
- Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
| | - Nathan E. Duncan
- Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
| | - Megan M. Jourdan
- Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
| | - Edit B. Olasz
- Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
| | - John E. Moulder
- Department of Radiation Oncology Center for Medical Countermeasures against Radiological Terrorism, Medical College of Wisconsin, Milwaukee, Wisconsin, and Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
| | - Brian L. Fish
- Department of Radiation Oncology Center for Medical Countermeasures against Radiological Terrorism, Medical College of Wisconsin, Milwaukee, Wisconsin, and Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
| | - Marylou Mäder
- Department of Radiation Oncology Center for Medical Countermeasures against Radiological Terrorism, Medical College of Wisconsin, Milwaukee, Wisconsin, and Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
| | - Jozef Lazar
- Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
| | - Zelmira Lazarova
- Department of Dermatology, Boston University School of Medicine, Boston, MA, USA
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21
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Kim JH, Kolozsvary AJJ, Jenrow KA, Brown SL. Mechanisms of radiation-induced skin injury and implications for future clinical trials. Int J Radiat Biol 2013; 89:311-8. [DOI: 10.3109/09553002.2013.765055] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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22
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Otterson MF, Nie L, Schmidt JL, Link BJ, Jovanovic N, Lyros O, Rafiee P. EUK-207 protects human intestinal microvascular endothelial cells (HIMEC) against irradiation-induced apoptosis through the Bcl2 pathway. Life Sci 2012; 91:771-82. [PMID: 22940617 PMCID: PMC3520131 DOI: 10.1016/j.lfs.2012.08.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 08/04/2012] [Accepted: 08/08/2012] [Indexed: 01/16/2023]
Abstract
AIM To elucidate the signaling mechanisms involved in the protective effect of EUK-207 against irradiation-induced cellular damage and apoptosis in human intestinal microvasculature endothelial cells (HIMEC). METHODS HIMECs were irradiated and treated with EUK-207. Using hydroethidine and DCF-DA fluorescent probe the intracellular superoxide and reactive oxygen species (ROS) were determined. By real-time PCR and western blotting caspase-3, Bcl2 and Bax genes and proteins were analyzed. Proliferation was determined by [(3)H]-thymidine uptake. Immunofluorescence staining was used for translocation of p65 NFκB subunit. KEY FINDING Irradiation increased ROS production, apoptosis, Bax, Caspase3 and NFkB activity in HIMEC and inhibited cell survival/growth/proliferation. EUK-207 restored the endothelial functions, markedly inhibited the ROS, up-regulated the Bcl2 and down-regulated Bax and prevented NFκB caspase 3 activity in HIMEC. SIGNIFICANCE HIMEC provide a novel model to define the effect of irradiation induced endothelial dysfunction. Our findings suggest that EUK-207 effectively inhibits the damaging effect of irradiation.
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Affiliation(s)
- Mary F. Otterson
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Linghui Nie
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jamie L. Schmidt
- Division of Gastroenterology and Hepathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Benjamin J. Link
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Nebojsa Jovanovic
- Division of Gastroenterology and Hepathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Orestis Lyros
- Division of Gastroenterology and Hepathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Parvaneh Rafiee
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
- Division of Gastroenterology and Hepathology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Kim JH, Kolozsvary A, Jenrow KA, Brown SL. Plerixafor, a CXCR4 Antagonist, Mitigates Skin Radiation-Induced Injury in Mice. Radiat Res 2012; 178:202-6. [DOI: 10.1667/rr2886.1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Zhang S, Song C, Zhou J, Xie L, Meng X, Liu P, Cao J, Zhang X, Ding WQ, Wu J. Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats. Radiat Oncol 2012; 7:4. [PMID: 22247972 PMCID: PMC3282628 DOI: 10.1186/1748-717x-7-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 01/17/2012] [Indexed: 12/31/2022] Open
Abstract
Objective Radiation-induced skin injury remains a serious concern for radiation therapy. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been reported to have potential antioxidant and anti-apoptotic properties. However, the role of HO-1 in radiation-induced skin damage remains unclear. This study aims to elucidate the effects of HO-1 on radiation-induced skin injury in rats. Methods A control adenovirus (Ad-EGFP) and a recombinant adenovirus (Ad-HO1-EGFP) were constructed. Rats were irradiated to the buttock skin with a single dose of 45 Gy followed by a subcutaneous injection of PBS, 5 × 109 genomic copies of Ad-EGFP or Ad-HO1-EGFP (n = 8). After treatment, the skin MDA concentration, SOD activity and apoptosis were measured. The expression of antioxidant and pro-apoptotic genes was determined by RT-PCR and real-time PCR. Skin reactions were measured at regular intervals using the semi-quantitative skin injury score. Results Subcutaneous injection of Ad-HO1-EGFP infected both epidermal and dermal cells and could spread to the surrounding regions. Radiation exposure upregulated the transcription of the antioxidant enzyme genes, including SOD-1, GPx2 and endogenous HO-1. HO-1 overexpression decreased lipid peroxidation and inhibited the induction of ROS scavenging proteins. Moreover, HO-1 exerted an anti-apoptotic effect by suppressing FAS and FASL expression. Subcutaneous injection of Ad-HO1-EGFP demonstrated significant improvement in radiation-induced skin injury. Conclusions The present study provides evidences for the protective role of HO-1 in alleviating radiation-induced skin damage in rats, which is helpful for the development of therapy for radiation-induced skin injury.
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Affiliation(s)
- Shuyu Zhang
- School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, China
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Abstract
Radiation leaves a fairly characteristic footprint in biological materials, but this is rapidly all but obliterated by the canonical biological responses to the radiation damage. The innate immune recognition systems that sense "danger" through direct radiation damage and through associated collateral damage set in motion a chain of events that, in a tissue compromised by radiation, often unwittingly result in oscillating waves of molecular and cellular responses as tissues attempt to heal. Understanding "nature's whispers" that inform on these processes will lead to novel forms of intervention targeted more precisely towards modifying them in an appropriate and timely fashion so as to improve the healing process and prevent or mitigate the development of acute and late effects of normal tissue radiation damage, whether it be accidental, as a result of a terrorist incident, or of therapeutic treatment of cancer. Here we attempt to discuss some of the non-free radical scavenging mechanisms that modify radiation responses and comment on where we see them within a conceptual framework of an evolving radiation-induced lesion.
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Affiliation(s)
- Kwanghee Kim
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA
| | - William H. McBride
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA
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Vorotnikova E, Rosenthal RA, Tries M, Doctrow SR, Braunhut SJ. Novel synthetic SOD/catalase mimetics can mitigate capillary endothelial cell apoptosis caused by ionizing radiation. Radiat Res 2010; 173:748-59. [PMID: 20518654 DOI: 10.1667/rr1948.1] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Numerous in vitro and in vivo studies have shown that the endothelial cells of the microvasculature of the lung and kidney are damaged by exposure to ionizing radiation, and this sustained endothelial cell injury is involved in the early and late radiation effects observed in these tissues. It is well accepted that ionizing radiation causes the generation of reactive oxygen species during exposure that results in damage to DNA and cellular organelles. It is more controversial, however, whether additional biochemical events or long-lived radicals occur and persist postirradiation that amplify and initiate new forms of cellular damage. Two families of Eukarion (EUK) compounds have been synthesized that possess superoxide dismutase (SOD), catalase and peroxidase activities. The Mn porphyrins are available orally whereas the salen Mn complexes are administered by injection. In the present study we have examined the ability of these SOD/catalase mimetics to prevent apoptosis of endothelial cells when administered 1 h postirradiation (mitigation). A range of salen Mn complex (EUK-189 and EUK-207) and Mn porphyrins (EUK-418, -423, -425, -450, -451, -452, -453) were used to treat endothelial cells 1 h after the cells received 2-20 Gy ionizing radiation in vitro. Two lead compounds, EUK-207 at a dose of 30 microM and EUK-451 at a dose of 10 microM, exhibited low toxicity and mitigated radiation-induced apoptosis. Future animal studies will test whether these compounds protect when administered after radiation exposure as would be done after a radiological accident or a terrorism event.
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Affiliation(s)
- Ekaterina Vorotnikova
- The Department of Biological Sciences, The University of Massachusetts, Lowell, MA 01854, USA
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Pollard JM, Reboucas JS, Durazo A, Kos I, Fike F, Panni M, Gralla EB, Valentine JS, Batinic-Haberle I, Gatti RA. Radioprotective effects of manganese-containing superoxide dismutase mimics on ataxia-telangiectasia cells. Free Radic Biol Med 2009; 47:250-60. [PMID: 19389472 PMCID: PMC3592562 DOI: 10.1016/j.freeradbiomed.2009.04.018] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2008] [Revised: 03/30/2009] [Accepted: 04/13/2009] [Indexed: 01/01/2023]
Abstract
We tested several classes of antioxidant manganese compounds for radioprotective effects using human lymphoblastoid cells: six porphyrins, three salens, and two cyclic polyamines. Radioprotection was evaluated by seven assays: XTT, annexin V and propidium iodide flow cytometry analysis, gamma-H2AX immunofluorescence, the neutral comet assay, dichlorofluorescein and dihydroethidium staining, resazurin, and colony survival assay. Two compounds were most effective in protecting wild-type and A-T cells against radiation-induced damage: MnMx-2-PyP-Calbio (a mixture of differently N-methylated MnT-2-PyP+ from Calbiochem) and MnTnHex-2-PyP. MnTnHex-2-PyP protected WT cells against radiation-induced apoptosis by 58% (p = 0.04), using XTT, and A-T cells by 39% (p = 0.01), using annexin V and propidium iodide staining. MnTnHex-2-PyP protected WT cells against DNA damage by 57% (p = 0.005), using gamma-H2AX immunofluorescence, and by 30% (p < 0.01), using neutral comet assay. MnTnHex-2-PyP is more lipophilic than MnMx-2-PyP-Calbio and is also >10-fold more SOD-active; consequently it is >50-fold more potent as a radioprotectant, as supported by six of the tests employed in this study. Thus, lipophilicity and antioxidant potency correlated with the magnitude of the beneficial radioprotectant effects observed. Our results identify a new class of porphyrinic radioprotectants for the general and radiosensitive populations and may also provide a new option for treating A-T patients.
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Affiliation(s)
- Julianne M Pollard
- Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Kim JH, Brown SL, Jenrow KA, Ryu S. Mechanisms of radiation-induced brain toxicity and implications for future clinical trials. J Neurooncol 2008; 87:279-86. [PMID: 18209952 DOI: 10.1007/s11060-008-9520-x] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2007] [Accepted: 01/02/2008] [Indexed: 12/27/2022]
Abstract
Radiation therapy is widely used in the treatment of primary malignant brain tumors and metastatic tumors of the brain with either curative or palliative intent. The limitation of cancer radiation therapy does not derive from the inability to ablate tumor, but rather to do so without excessively damaging the patient. Among the varieties of radiation-induced brain toxicities, it is the late delayed effects that lead to severe and irreversible neurological consequences. Following radiation exposure, late delayed effects within the CNS have been attributable to both parenchymal and vascular damage involving oligodendrocytes, neural progenitors, and endothelial cells. These reflect a dynamic process involving radiation-induced death of target cells and subsequent secondary reactive neuroinflammatory processes that are believed to lead to selective cell loss, tissue damage, and functional deficits. The progressive, late delayed damage to the brain after high-dose radiation is thought to be caused by radiation-induced long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines. Experimental studies suggest that radiation-induced brain injury can be successfully mitigated and treated with several well established drugs in wide clinical use which exert their effects by blocking pro-inflammatory cytokines and reactive oxygen species. This review highlights preclinical and early clinical data that are translatable for future clinical trials.
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Affiliation(s)
- Jae Ho Kim
- Department of Radiation Oncology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48025, USA
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