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Kundu M, Dey A, Dasgupta S. Replication stress response and radioresistance in lung cancer: Mechanistic insights and advanced therapeutic approaches. Curr Probl Cancer 2025; 56:101206. [PMID: 40267631 DOI: 10.1016/j.currproblcancer.2025.101206] [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: 10/24/2024] [Revised: 03/21/2025] [Accepted: 04/15/2025] [Indexed: 04/25/2025]
Abstract
Lung cancer, the leading cause of cancer mortality globally, comprises mainly non-small cell lung cancer and small cell lung cancer. Its pathogenesis involves genetic mutations, environmental exposures, chronic inflammation, and tumor microenvironment interactions. Critical genes like TP53, RB1, KRAS, and EGFR often mutate, driving uncontrolled cell growth. Radiation therapy, a primary treatment, faces challenges with radioresistance due to DNA repair mechanisms and replication stress responses. Emerging therapeutic strategies target DNA repair pathways, cell cycle checkpoints, and immune responses to enhance radiosensitivity and counteract resistance. Promising approaches include PARP inhibitors, CDK inhibitors, EGFR blockers, and immunotherapies combined with radiation. Advances in understanding these mechanisms are crucial for developing targeted therapies to improve lung cancer patient outcomes. The present review focuses on elucidating the intricate mechanisms of lung cancer pathogenesis and radioresistance, while highlighting novel therapeutic strategies designed to overcome these challenges and improve treatment efficacy.
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Affiliation(s)
- Moumita Kundu
- Center of Multidisciplinary Research and Innovations, Brainware University, Kolkata, West Bengal, India; Department of Pharmaceutical Technology, Brainware University, Kolkata, West Bengal, India
| | - Ankita Dey
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, West Bengal, India
| | - Sanjukta Dasgupta
- Center of Multidisciplinary Research and Innovations, Brainware University, Kolkata, West Bengal, India; Department of Biotechnology, Brainware University, Kolkata, West Bengal, India.
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2
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Deng Z, Guo J, Zhu Z, Qing Q, Wan D, Lei P, Liu Q, Huang B. The effect and mechanism of atorvastatin regulating PI3K-Akt-mTOR pathway on radiosensitivity of hepatocellular carcinoma cells. Toxicol Res (Camb) 2025; 14:tfae202. [PMID: 40012843 PMCID: PMC11851483 DOI: 10.1093/toxres/tfae202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 09/24/2024] [Accepted: 02/22/2025] [Indexed: 02/28/2025] Open
Abstract
Radiation therapy is an important method to treat liver cancer, but because of the strong DNA repair ability of liver cancer cells, even after receiving high doses of radiation still can not get satisfactory results. Atorvastatin (ATO) is a lipophilic and tissue-selective inhibitor of HMG-CoA reductase whose anticancer effects have been validated in various cells, but its effect on the radiation sensitivity of hepatocellular carcinoma cells remains unclear. Therefore, Therefore, this study explored the radiosensitivity of ATO and its possible mechanism by pretreating HepG2 with ATO and collecting HepG2 cells after irradiation. It was found that atorvastatin can not only affect the survival of liver cancer cells when used alone, but also enhance the radiation sensitivity of HepG2 cells. The study found that ATO significantly exacerbated the inhibitory effects of IR on the growth, proliferation, and migration of HepG2 cells. Measurement of ROS, SOD, GPx, and MDA levels indicated that ATO enhanced IR-induced oxidative stress, further promoted the decrease of Mitochondrial Membrane Potential, increased the rate of apoptosis in HepG2, upregulating pro-apoptotic proteins Bax and Cleaved-Caspase 3, and downregulating anti-apoptotic proteins Bcl-2. Western blot analysis showed that the PI3K-Akt-mTOR pathway was inhibited, leading to the activation of cytotoxic autophagy in HepG2 and an increase in the expression of the LC-3II protein. In summary, ATO, in combination with IR, enhances the oxidative stress response of HepG2 induced by IR, promotes autophagy by inhibiting the PI3K-Akt-mTOR pathway, and thereby potentially enhances the radiosensitivity of HepG2 as a pharmacological intervention.
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Affiliation(s)
- Zhengzheng Deng
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
| | - Jinjing Guo
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
| | - Zihao Zhu
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
| | - Qiancheng Qing
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
| | - Dangting Wan
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
- Guangdong Maoming Health Vocational College, No. 1 Anle East Road, Maoming City, Guangdong 525000, P.R. China
| | - Pengyuan Lei
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
| | - Qi Liu
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
| | - Bo Huang
- College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421000, P.R. China
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Nemec-Bakk AS, Sridharan V, Willey JS, Koturbash I, Williams DK, Chesal M, Patel CM, Borg AM, Reno K, Gifford G, Newhauser W, Williams J, Chancellor JC, Boerma M. Sex-specific effects on the heart from combined exposure to simulated galactic cosmic radiation and hindlimb unloading. LIFE SCIENCES IN SPACE RESEARCH 2025; 44:38-46. [PMID: 39864910 PMCID: PMC11770252 DOI: 10.1016/j.lssr.2024.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 11/28/2024] [Accepted: 12/04/2024] [Indexed: 01/28/2025]
Abstract
Future long duration space missions will expose astronauts to higher doses of galactic cosmic radiation (GCR) than those experienced on the international space station. Recent studies have demonstrated astronauts may be at risk for cardiovascular complications due to increased radiation exposure and fluid shift from microgravity. However, there is a lack of direct evidence on how the cardiovascular system is affected by GCR and microgravity since no astronauts have been exposed to exploratory mission relevant GCR doses. Therefore, we utilized a ground-based mouse model to determine the cardiovascular risks for space radiation exposure while the mice were simultaneously hindlimb suspended to mimic microgravity. 6-month-old male and female C57BL/6 mice were exposed to an absorbed dose of 0 Gy, 0.5 Gy, or 1.5 Gy simulated GCR (GCRsim) that comprised beams of 5 ions at NASA's Space Radiation Laboratory. Subcohorts of mice were hindlimb unloaded (HLU), starting 5 days before GCRsim until the completion of radiation exposure. GCRsim + HLU was performed over 8 hours (0.5 Gy) or 24 hours (1.5 Gy). After completion of GCRsim and HLU, mice were shipped to UAMS for long-term observation. Cardiac function was measured using high resolution ultrasound at 6 and 9 months after exposure. Tissues were collected after the final ultrasound and prepared for further analysis. Female mice exposed to 1.5 Gy + HLU demonstrated a significant increase in body weight compared to ground controls months after GCR exposure; however, there was no change in male body weights. Cardiac ultrasound revealed 0.5 Gy GCRsim decreased left ventricular (LV) mass, LV posterior wall thickness in diastole, and systole in males 6 months after exposure. In females, 1.5 Gy + HLU significantly increased LV posterior wall thickness in diastole and systole at 6 months. These changes in ultrasound measurements were no longer seen at 9 months. Moreover, at 9 months there was no change in total collagen content or density of the capillary network in the heart. Lastly, the combination of GCRsim and HLU influenced immune cell markers in the heart of female mice. These data suggest that combined simulated GCR and microgravity result in minor, yet statistically significant sex-dependent changes to body weight and cardiac structure.
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Affiliation(s)
- A S Nemec-Bakk
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - V Sridharan
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - J S Willey
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - I Koturbash
- Department of Environmental Health Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - D K Williams
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - M Chesal
- Department of Physics & Astronomy, Louisiana State University, Baton Rouge, Louisiana, USA
| | - C M Patel
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - A M Borg
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - K Reno
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - G Gifford
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - W Newhauser
- Department of Physics & Astronomy, Louisiana State University, Baton Rouge, Louisiana, USA
| | - J Williams
- Departments of Environmental Medicine and Radiation Oncology, University of Rochester, Medical Center, Rochester, New York, USA
| | - J C Chancellor
- Department of Physics & Astronomy, Louisiana State University, Baton Rouge, Louisiana, USA; Department of Preventive Medicine & Population Health, University of Texas Medical Branch, Galveston, Texas, USA; Outer Space Institute, University of British Columbia, Vancouver, Canada
| | - M Boerma
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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Suwanprakorn N, Shin KJ, Tran PH, Truong NT, Kim KS, Yoo HJ, Yang SG. Transcriptomic analysis of embryonic mouse hypothalamic N38 cells exposed to high-energy protons and/or simulated microgravity. Heliyon 2024; 10:e39533. [PMID: 39506968 PMCID: PMC11538749 DOI: 10.1016/j.heliyon.2024.e39533] [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: 07/26/2024] [Revised: 10/10/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024] Open
Abstract
Purpose Space exploration poses unique challenges to astronauts, especially the effects of space radiation and microgravity (μG). Understanding molecular responses to these factors is crucial for ensuring astronaut health, and this study aimed to identify transcriptomic changes in mouse hypothalamic cell line N38 (mHypoE-N38) caused by simulated space environments. Method Four experimental groups were established, namely, a ground condition group (GC; the control group), a proton irradiated group (the space radiation group), a simulated μG group, and a proton irradiated × simulated μG group (the combination group). RNA sequencing and quantitative real-time polymerase chain reaction were performed to investigate key altered genes and to validate them. Results Three hundred and fifty-five differentially expressed genes were identified. Notably, the expressions of UCN2 and UGT1A5 genes were upregulated in all three experimental groups, suggesting a shared regulatory mechanism with potential consequences for brain function during space missions. Moreover, the study revealed significant alterations in genes belonging to the USP17 and ZSCAN4 families, indicating active response to DNA damage and telomere maintenance. PCR results validated that UGT1A5, USP17 family, and ZSCAN4 families (ZSCAN4C, ZSCAN4D, and ZSCAN4F) were significantly upregulated at the mRNA level in the combination group, while UCN2, ZSCAN4A, and ZSCAN4B were not reproduced. Conclusion The present study on mHypoE-N38 cells exposed to space environments revealed a complex molecular narrative with disease-oriented implications. The knowledge gained might serve as a cornerstone for developing strategies to mitigate potential health risks associated with extended exposure to space-related stressors.
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Affiliation(s)
- Nattha Suwanprakorn
- Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea
- Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon, 22332, Republic of Korea
| | - Kyung-Ju Shin
- Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea
- Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon, 22332, Republic of Korea
| | - Phuong Hoa Tran
- Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea
- Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon, 22332, Republic of Korea
| | - Ngoc Thuan Truong
- Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea
- Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon, 22332, Republic of Korea
| | - Kyu-Sung Kim
- Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea
- Department of Otorhinolaryngology, Head and Neck Surgery, Inha University Hospital, Incheon, 22332, Republic of Korea
| | - Hye Jin Yoo
- Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon, 22332, Republic of Korea
- Institute for Specialized Teaching and Research (INSTAR), Inha University, Incheon, 22332, Republic of Korea
| | - Su-Geun Yang
- Inha Institute of Aerospace Medicine, Inha University College of Medicine, Incheon, 22332, Republic of Korea
- Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon, 22332, Republic of Korea
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Wang S, Cheng M, Wang S, Jiang W, Yang F, Shen X, Zhang L, Yan X, Jiang B, Fan K. A Self-Catalytic NO/O 2 Gas-Releasing Nanozyme for Radiotherapy Sensitization through Vascular Normalization and Hypoxia Relief. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2403921. [PMID: 39101290 DOI: 10.1002/adma.202403921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 06/29/2024] [Indexed: 08/06/2024]
Abstract
Radiotherapy (RT), essential for treating various cancers, faces challenges from tumor hypoxia, which induces radioresistance. A tumor-targeted "prosthetic-Arginine" coassembled nanozyme system, engineered to catalytically generate nitric oxide (NO) and oxygen (O2) in the tumor microenvironment (TME), overcoming hypoxia and enhancing radiosensitivity is presented. This system integrates the prosthetic heme of nitric oxide synthase (NOS) and catalase (CAT) with NO-donating Fmoc-protected Arginine and Ru3+ ions, creating HRRu nanozymes that merge NOS and CAT functionalities. Surface modification with human heavy chain ferritin (HFn) improves the targeting ability of nanozymes (HRRu-HFn) to tumor tissues. In the TME, strategic arginine incorporation within the nanozyme allows autonomous O2 and NO release, triggered by endogenous hydrogen peroxide, elevating NO and O2 levels to normalize vasculature and improve blood perfusion, thus mitigating hypoxia. Employing the intrinsic O2-transporting ability of heme, HRRu-HFn nanozymes also deliver O2 directly to the tumor site. Utilizing esophageal squamous cell carcinoma as a tumor model, the studies reveal that the synergistic functions of NO and O2 production, alongside targeted delivery, enable the HRRu-HFn nanozymes to combat tumor hypoxia and potentiate radiotherapy. This HRRu-HFn nanozyme based approach holds the potential to reduce the radiation dose required and minimize side effects associated with conventional radiotherapy.
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Affiliation(s)
- Shuyu Wang
- Nanozyme Laboratory in Zhongyuan, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Miaomiao Cheng
- Nanozyme Laboratory in Zhongyuan, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Shenghui Wang
- Nanozyme Laboratory in Zhongyuan, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Wei Jiang
- Nanozyme Laboratory in Zhongyuan, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
| | - Feifei Yang
- College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, China
| | - Xiaomei Shen
- College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330022, China
| | - Lirong Zhang
- State Key Laboratory of Esophageal Cancer Prevention &Treatment, Henan, 450001, China
| | - Xiyun Yan
- Nanozyme Laboratory in Zhongyuan, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, 451163, China
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Bing Jiang
- Nanozyme Laboratory in Zhongyuan, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, 451163, China
| | - Kelong Fan
- Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, 451163, China
- CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
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6
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Wang S, Cheng M, Wang S, Jiang W, Yang F, Shen X, Zhang L, Yan X, Jiang B, Fan K. A Self‐Catalytic NO/O 2 Gas‐Releasing Nanozyme for Radiotherapy Sensitization through Vascular Normalization and Hypoxia Relief. ADVANCED MATERIALS 2024. [DOI: doi：10.1002/adma.202403921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Indexed: 04/16/2025]
Abstract
AbstractRadiotherapy (RT), essential for treating various cancers, faces challenges from tumor hypoxia, which induces radioresistance. A tumor‐targeted “prosthetic‐Arginine” coassembled nanozyme system, engineered to catalytically generate nitric oxide (NO) and oxygen (O2) in the tumor microenvironment (TME), overcoming hypoxia and enhancing radiosensitivity is presented. This system integrates the prosthetic heme of nitric oxide synthase (NOS) and catalase (CAT) with NO‐donating Fmoc‐protected Arginine and Ru3+ ions, creating HRRu nanozymes that merge NOS and CAT functionalities. Surface modification with human heavy chain ferritin (HFn) improves the targeting ability of nanozymes (HRRu‐HFn) to tumor tissues. In the TME, strategic arginine incorporation within the nanozyme allows autonomous O2 and NO release, triggered by endogenous hydrogen peroxide, elevating NO and O2 levels to normalize vasculature and improve blood perfusion, thus mitigating hypoxia. Employing the intrinsic O2‐transporting ability of heme, HRRu‐HFn nanozymes also deliver O2 directly to the tumor site. Utilizing esophageal squamous cell carcinoma as a tumor model, the studies reveal that the synergistic functions of NO and O2 production, alongside targeted delivery, enable the HRRu‐HFn nanozymes to combat tumor hypoxia and potentiate radiotherapy. This HRRu‐HFn nanozyme based approach holds the potential to reduce the radiation dose required and minimize side effects associated with conventional radiotherapy.
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Affiliation(s)
- Shuyu Wang
- Nanozyme Laboratory in Zhongyuan School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan 450001 China
| | - Miaomiao Cheng
- Nanozyme Laboratory in Zhongyuan School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan 450001 China
| | - Shenghui Wang
- Nanozyme Laboratory in Zhongyuan School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan 450001 China
| | - Wei Jiang
- Nanozyme Laboratory in Zhongyuan School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan 450001 China
| | - Feifei Yang
- College of Chemistry and Chemical Engineering Jiangxi Normal University Nanchang 330022 China
| | - Xiaomei Shen
- College of Chemistry and Chemical Engineering Jiangxi Normal University Nanchang 330022 China
| | - Lirong Zhang
- State Key Laboratory of Esophageal Cancer Prevention &Treatment Henan 450001 China
| | - Xiyun Yan
- Nanozyme Laboratory in Zhongyuan School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan 450001 China
- Nanozyme Laboratory in Zhongyuan Henan Academy of Innovations in Medical Science Zhengzhou Henan 451163 China
- CAS Engineering Laboratory for Nanozyme Key Laboratory of Biomacromolecules (CAS) CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China
| | - Bing Jiang
- Nanozyme Laboratory in Zhongyuan School of Basic Medical Sciences Zhengzhou University Zhengzhou Henan 450001 China
- Nanozyme Laboratory in Zhongyuan Henan Academy of Innovations in Medical Science Zhengzhou Henan 451163 China
| | - Kelong Fan
- Nanozyme Laboratory in Zhongyuan Henan Academy of Innovations in Medical Science Zhengzhou Henan 451163 China
- CAS Engineering Laboratory for Nanozyme Key Laboratory of Biomacromolecules (CAS) CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China
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Zhao L, Li M, Shen C, Luo Y, Hou X, Qi Y, Huang Z, Li W, Gao L, Wu M, Luo Y. Nano-Assisted Radiotherapy Strategies: New Opportunities for Treatment of Non-Small Cell Lung Cancer. RESEARCH (WASHINGTON, D.C.) 2024; 7:0429. [PMID: 39045421 PMCID: PMC11265788 DOI: 10.34133/research.0429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 06/26/2024] [Indexed: 07/25/2024]
Abstract
Lung cancer is the second most commonly diagnosed cancer and a leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the most prevalent type. Over 70% of lung cancer patients require radiotherapy (RT), which operates through direct and indirect mechanisms to treat cancer. However, RT can damage healthy tissues and encounter radiological resistance, making it crucial to enhance its precision to optimize treatment outcomes, minimize side effects, and overcome radioresistance. Integrating nanotechnology into RT presents a promising method to increase its efficacy. This review explores various nano-assisted RT strategies aimed at achieving precision treatment. These include using nanomaterials as radiosensitizers, applying nanotechnology to modify the tumor microenvironment, and employing nano-based radioprotectors and radiation-treated cell products for indirect cancer RT. We also explore recent advancements in nano-assisted RT for NSCLC, such as biomimetic targeting that alters mesenchymal stromal cells, magnetic targeting strategies, and nanosensitization with high-atomic number nanomaterials. Finally, we address the existing challenges and future directions of precision RT using nanotechnology, highlighting its potential clinical applications.
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Affiliation(s)
- Lihong Zhao
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Mei Li
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Chen Shen
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Yurui Luo
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Xiaoming Hou
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Yu Qi
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Ziwei Huang
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Wei Li
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Lanyang Gao
- The Affiliated Hospital ofSouthwest Medical University, Southwest Medical University, Luzhou 646000, China
| | - Min Wu
- West China Hospital,
Sichuan University, Chengdu 610041, China
| | - Yao Luo
- West China Hospital,
Sichuan University, Chengdu 610041, China
- Zigong First People’s Hospital, Zigong 643000, China
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8
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Forenzo C, Larsen J. Bridging clinical radiotherapy and space radiation therapeutics through reactive oxygen species (ROS)-triggered delivery. Free Radic Biol Med 2024; 219:88-103. [PMID: 38631648 DOI: 10.1016/j.freeradbiomed.2024.04.219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/15/2024] [Accepted: 04/09/2024] [Indexed: 04/19/2024]
Abstract
This review explores the convergence of clinical radiotherapy and space radiation therapeutics, focusing on ionizing radiation (IR)-generated reactive oxygen species (ROS). IR, with high-energy particles, induces precise cellular damage, particularly in cancer treatments. The paper discusses parallels between clinical and space IR, highlighting unique characteristics of high-charge and energy particles in space and potential health risks for astronauts. Emphasizing the parallel occurrence of ROS generation in both clinical and space contexts, the review identifies ROS as a crucial factor with dual roles in cellular responses and potential disease initiation. The analysis covers ROS generation mechanisms, variations, and similarities in terrestrial and extraterrestrial environments leading to innovative ROS-responsive delivery systems adaptable for both clinical and space applications. The paper concludes by discussing applications of personalized ROS-triggered therapeutic approaches and discussing the challenges and prospects of implementing these strategies in clinical radiotherapy and extraterrestrial missions. Overall, it underscores the potential of ROS-targeted delivery for advancing therapeutic strategies in terrestrial clinical settings and space exploration, contributing to human health improvement on Earth and beyond.
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Affiliation(s)
- Chloe Forenzo
- Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC, 29631, USA
| | - Jessica Larsen
- Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC, 29631, USA; Department of Bioengineering, Clemson University, Clemson, SC, 29631, USA.
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9
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Yao Y, Xu R, Shao W, Tan J, Wang S, Chen S, Zhuang A, Liu X, Jia R. A Novel Nanozyme to Enhance Radiotherapy Effects by Lactic Acid Scavenging, ROS Generation, and Hypoxia Mitigation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2403107. [PMID: 38704679 PMCID: PMC11234405 DOI: 10.1002/advs.202403107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Indexed: 05/07/2024]
Abstract
Uveal melanoma (UM) is a leading intraocular malignancy with a high 5-year mortality rate, and radiotherapy is the primary approach for UM treatment. However, the elevated lactic acid, deficiency in ROS, and hypoxic tumor microenvironment have severely reduced the radiotherapy outcomes. Hence, this study devised a novel CoMnFe-layered double oxides (LDO) nanosheet with multienzyme activities for UM radiotherapy enhancement. On one hand, LDO nanozyme can catalyze hydrogen peroxide (H2O2) in the tumor microenvironment into oxygen and reactive oxygen species (ROS), significantly boosting ROS production during radiotherapy. Simultaneously, LDO efficiently scavenged lactic acid, thereby impeding the DNA and protein repair in tumor cells to synergistically enhance the effect of radiotherapy. Moreover, density functional theory (DFT) calculations decoded the transformation pathway from lactic to pyruvic acid, elucidating a previously unexplored facet of nanozyme activity. The introduction of this innovative nanomaterial paves the way for a novel, targeted, and highly effective therapeutic approach, offering new avenues for the management of UM and other cancer types.
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Affiliation(s)
- Yiran Yao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Ru Xu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China
| | - Weihuan Shao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Ji Tan
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China
| | - Shaoyun Wang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Shuhan Chen
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China
| | - Ai Zhuang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
| | - Xuanyong Liu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China
| | - Renbing Jia
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P. R. China
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10
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Luitel K, Siteni S, Barron S, Shay JW. Simulated galactic cosmic radiation-induced cancer progression in mice. LIFE SCIENCES IN SPACE RESEARCH 2024; 41:43-51. [PMID: 38670651 DOI: 10.1016/j.lssr.2024.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/29/2023] [Accepted: 01/28/2024] [Indexed: 04/28/2024]
Abstract
Prolonged manned space flight exposure risks to galactic comic radiation, has led to uncertainties in a variety of health risks. Our previous work, utilizing either single ion or multiple ion radiation exposure conducted at the NSRL (NASA Space Radiation Laboratory, Brookhaven, NY) demonstrated that HZE ion components of the GCR result in persistent inflammatory signaling, increased mutations, and higher rates of cancer initiation and progression. With the development of the 33-beam galactic cosmic radiation simulations (GCRsim) at the NSRL, we can more closely test on earth the radiation environment found in space. With a previously used lung cancer susceptible mouse model (K-rasLA-1), we performed acute exposure experiments lasting 1-2 h, and chronic exposure experiments lasting 2-6 weeks with a total dose of 50 cGy and 75 cGy. We obtained histological samples from a subset of mice 100 days post-irradiation, and the remaining mice were monitored for overall survival up to 1-year post-irradiation. When we compared acute exposures (1-2 hrs.) and chronic exposure (2-6 weeks), we found a trend in the increase of lung adenocarcinoma respectively for a total dose of 50 cGy and 75 cGy. Furthermore, when we added neutron exposure to the 75 cGy of GCRsim, we saw a further increase in the incidence of adenocarcinoma. We interpret these findings to suggest that the risks of carcinogenesis are heightened with doses anticipated during a round trip to Mars, and this risk is magnified when coupled with extra neutron exposure that are expected on the Martian surface. We also observed that risks are reduced when the NASA official 33-beam GCR simulations are provided at high dose rates compared to low dose rates.
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Affiliation(s)
- Krishna Luitel
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Silvia Siteni
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Summer Barron
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jerry W Shay
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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11
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Mason CE, Sierra MA, Feng HJ, Bailey SM. Telomeres and aging: on and off the planet! Biogerontology 2024; 25:313-327. [PMID: 38581556 PMCID: PMC10998805 DOI: 10.1007/s10522-024-10098-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2024] [Indexed: 04/08/2024]
Abstract
Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.
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Affiliation(s)
- Christopher E Mason
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
- The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA
| | - Maria A Sierra
- The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA
- Tri-Institutional Computational Biology & Medicine Program, Weill Cornell Medicine, New York, NY, USA
| | - Henry J Feng
- Department of Biological Sciences, Columbia University, New York, NY, USA
- Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Susan M Bailey
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.
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12
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Cucinotta FA. Non-targeted effects and space radiation risks for astronauts on multiple International Space Station and lunar missions. LIFE SCIENCES IN SPACE RESEARCH 2024; 40:166-175. [PMID: 38245342 DOI: 10.1016/j.lssr.2023.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 01/22/2024]
Abstract
Future space travel to the earth's moon or the planet Mars will likely lead to the selection of experienced International Space Station (ISS) or lunar crew persons for subsequent lunar or mars missions. Major concerns for space travel are galactic cosmic ray (GCR) risks of cancer and circulatory diseases. However large uncertainties in risk prediction occur due to the quantitative and qualitative differences in heavy ion microscopic energy deposition leading to differences in biological effects compared to low LET radiation. In addition, there are sparse radiobiology data and absence of epidemiology data for heavy ions and other high LET radiation. Non-targeted effects (NTEs) are found in radiobiology studies to increase the biological effectiveness of high LET radiation at low dose for cancer related endpoints. In this paper the most recent version of the NASA Space Cancer Risk model (NSCR-2022) is used to predict mission risks while considering NTEs in solid cancer risk predictions. I discuss predictions of space radiation risks of cancer and circulatory disease mortality for US Whites and US Asian-Pacific Islander (API) populations for 6-month ISS, 80-day lunar missions, and combined ISS-lunar mission. Model predictions suggest NTE increase cancer risks by about ∼2.3 fold over a model that ignores NTEs. US API are predicted to have a lower cancer risks of about 30% compared to US Whites. Cancer risks are slightly less than additive for multiple missions, which is due to the decease of risk with age of exposure and the increased competition with background risks as radiation risks increase. The inclusion of circulatory risks increases mortality estimates about 25% and 37% for females and males, respectively in the model ignoring NTEs, and 20% and 30% when NTEs are assumed to modify solid cancer risk. The predictions made here for combined ISS and lunar missions suggest risks are within risk limit recommendations by the National Council on Radiation Protection and Measurements (NCRP) for such missions.
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Affiliation(s)
- Francis A Cucinotta
- Univerity of Nevada Las Vegas, Las Vegas, NV, 89154, United States of America.
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13
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Cahoon DS, Rabin BM, Fisher DR, Shukitt-Hale B. Effects of HZE-Particle Exposure Location and Energy on Brain Inflammation and Oxidative Stress in Rats. Radiat Res 2023; 200:431-443. [PMID: 37758038 DOI: 10.1667/rade-22-00041.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 08/24/2023] [Indexed: 10/03/2023]
Abstract
Astronauts on exploratory missions will be exposed to particle radiation of high energy and charge (HZE particles), which have been shown to produce neurochemical and performance deficits in animal models. Exposure to HZE particles can produce both targeted effects, resulting from direct ionization of atoms along the particle track, and non-targeted effects (NTEs) in cells that are distant from the track, extending the range of potential damage beyond the site of irradiation. While recent work suggests that NTEs are primarily responsible for changes in cognitive function after HZE exposures, the relative contributions of targeted and non-targeted effects to neurochemical changes after HZE exposures are unclear. The present experiment was designed to further explore the role of targeted and non-targeted effects on HZE-induced neurochemical changes (inflammation and oxidative stress) by evaluating the effects of exposure location and particle energy/linear energy transfer (LET). Forty-six male Sprague-Dawley rats received head-only or body-only exposures to 56Fe particles [600 MeV/n (75 cGy) or 1,000 MeV/n (100 cGy)] or 48Ti particles [500 MeV/n (50 cGy) or 1,100 MeV/n (75 cGy)] or no irradiation (0 cGy). Twenty-four h after irradiation, rats were euthanized, and the brain was dissected for analysis of HZE-particle-induced neurochemical changes in the hippocampus and frontal cortex. Results showed that exposure to 56Fe and 48Ti ions produced changes in measurements of brain inflammation [glial fibrillary astrocyte protein (GFAP)], oxidative stress [NADPH-oxidoreductase-2 (NOX2)] and antioxidant enzymes [superoxide dismutase (SOD), glutathione S-transferase (GST), nuclear factor erythroid 2-related factor 2 (Nrf2)]. However, radiation effects varied depending upon the specific measurement, brain region, and exposure location. Although overall exposures of the head produced more detrimental changes in neuroinflammation and oxidative stress than exposures of the body, body-only exposures also produced changes relative to no irradiation, and the effect of particle energy/LET on neurochemical changes was minimal. Results indicate that both targeted and non-targeted effects are important contributors to neurochemical changes after head-only exposure. However, because there were no consistent neurochemical changes as a function of changes in track structure after head-only exposures, the role of direct effects on neuronal function is uncertain. Therefore, these findings, although in an animal model, suggest that NTEs should be considered in the estimation of risk to the central nervous system (CNS) and development of countermeasures.
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Affiliation(s)
- Danielle S Cahoon
- USDA-ARS, Human Nutrition Research Center on Aging at Tufts University, Boston, Maryland 02111
| | - Bernard M Rabin
- Department of Psychology, University of Maryland, Baltimore County, Baltimore, Maryland 21250
| | - Derek R Fisher
- USDA-ARS, Human Nutrition Research Center on Aging at Tufts University, Boston, Maryland 02111
| | - Barbara Shukitt-Hale
- USDA-ARS, Human Nutrition Research Center on Aging at Tufts University, Boston, Maryland 02111
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14
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Melia E, Parsons J. DNA damage and repair dependencies of ionising radiation modalities. Biosci Rep 2023; 43:BSR20222586. [PMID: 37695845 PMCID: PMC10548165 DOI: 10.1042/bsr20222586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/18/2023] [Accepted: 09/11/2023] [Indexed: 09/13/2023] Open
Abstract
Radiotherapy is utilised in the treatment of ∼50% of all human cancers, which predominantly employs photon radiation. However, particle radiotherapy elicits significant benefits over conventional photons due to more precise dose deposition and increased linear energy transfer (LET) that generates an enhanced therapeutic response. Specifically, proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) are characterised by a Bragg peak, which generates a low entrance radiation dose, with the majority of the energy deposition being defined within a small region which can be specifically targeted to the tumour, followed by a low exit dose. PBT is deemed relatively low-LET whereas CIRT is more densely ionising and therefore high LET. Despite the radiotherapy type, tumour cell killing relies heavily on the introduction of DNA damage that overwhelms the repair capacity of the tumour cells. It is known that DNA damage complexity increases with LET that leads to enhanced biological effectiveness, although the specific DNA repair pathways that are activated following the different radiation sources is unclear. This knowledge is required to determine whether specific proteins and enzymes within these pathways can be targeted to further increase the efficacy of the radiation. In this review, we provide an overview of the different radiation modalities and the DNA repair pathways that are responsive to these. We also provide up-to-date knowledge of studies examining the impact of LET and DNA damage complexity on DNA repair pathway choice, followed by evidence on how enzymes within these pathways could potentially be therapeutically exploited to further increase tumour radiosensitivity, and therefore radiotherapy efficacy.
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Affiliation(s)
- Emma Melia
- Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K
| | - Jason L. Parsons
- Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K
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15
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Tavakol DN, Nash TR, Kim Y, He S, Fleischer S, Graney PL, Brown JA, Liberman M, Tamargo M, Harken A, Ferrando AA, Amundson S, Garty G, Azizi E, Leong KW, Brenner DJ, Vunjak-Novakovic G. Modeling and countering the effects of cosmic radiation using bioengineered human tissues. Biomaterials 2023; 301:122267. [PMID: 37633022 PMCID: PMC10528250 DOI: 10.1016/j.biomaterials.2023.122267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/28/2023]
Abstract
Cosmic radiation is the most serious risk that will be encountered during the planned missions to the Moon and Mars. There is a compelling need to understand the effects, safety thresholds, and mechanisms of radiation damage in human tissues, in order to develop measures for radiation protection during extended space travel. As animal models fail to recapitulate the molecular changes in astronauts, engineered human tissues and "organs-on-chips" are valuable tools for studying effects of radiation in vitro. We have developed a bioengineered tissue platform for studying radiation damage in individualized settings. To demonstrate its utility, we determined the effects of radiation using engineered models of two human tissues known to be radiosensitive: engineered cardiac tissues (eCT, a target of chronic radiation damage) and engineered bone marrow (eBM, a target of acute radiation damage). We report the effects of high-dose neutrons, a proxy for simulated galactic cosmic rays, on the expression of key genes implicated in tissue responses to ionizing radiation, phenotypic and functional changes in both tissues, and proof-of-principle application of radioprotective agents. We further determined the extent of inflammatory, oxidative stress, and matrix remodeling gene expression changes, and found that these changes were associated with an early hypertrophic phenotype in eCT and myeloid skewing in eBM. We propose that individualized models of human tissues have potential to provide insights into the effects and mechanisms of radiation during deep-space missions and allow testing of radioprotective measures.
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Affiliation(s)
| | - Trevor R Nash
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Youngbin Kim
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Siyu He
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Sharon Fleischer
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Pamela L Graney
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Jessie A Brown
- Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
| | - Martin Liberman
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Manuel Tamargo
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Andrew Harken
- Center for Radiological Research, Columbia University, New York, NY 10032, USA
| | - Adolfo A Ferrando
- Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA
| | - Sally Amundson
- Center for Radiological Research, Columbia University, New York, NY 10032, USA
| | - Guy Garty
- Center for Radiological Research, Columbia University, New York, NY 10032, USA
| | - Elham Azizi
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Kam W Leong
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - David J Brenner
- Center for Radiological Research, Columbia University, New York, NY 10032, USA
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA; Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA.
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16
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Babu B, Pawar S, Mittal A, Kolanthai E, Neal CJ, Coathup M, Seal S. Nanotechnology enabled radioprotectants to reduce space radiation-induced reactive oxidative species. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1896. [PMID: 37190884 DOI: 10.1002/wnan.1896] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/04/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023]
Abstract
Interest in space exploration has seen substantial growth following recent launch and operation of modern space technologies. In particular, the possibility of travel beyond low earth orbit is seeing sustained support. However, future deep space travel requires addressing health concerns for crews under continuous, longer-term exposure to adverse environmental conditions. Among these challenges, radiation-induced health issues are a major concern. Their potential to induce chronic illness is further potentiated by the microgravity environment. While investigations into the physiological effects of space radiation are still under investigation, studies on model ionizing radiation conditions, in earth and micro-gravity conditions, can provide needed insight into relevant processes. Substantial formation of high, sustained reactive oxygen species (ROS) evolution during radiation exposure is a clear threat to physiological health of space travelers, producing indirect damage to various cell structures and requiring therapeutic address. Radioprotection toward the skeletal system components is essential to astronaut health, due to the high radio-absorption cross-section of bone mineral and local hematopoiesis. Nanotechnology can potentially function as radioprotectant and radiomitigating agents toward ROS and direct radiation damage. Nanoparticle compositions such as gold, silver, platinum, carbon-based materials, silica, transition metal dichalcogenides, and ceria have all shown potential as viable radioprotectants to mitigate space radiation effects with nanoceria further showing the ability to protect genetic material from oxidative damage in several studies. As research into space radiation-induced health problems develops, this review intends to provide insights into the nanomaterial design to ameliorate pathological effects from ionizing radiation exposure. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Nanotechnology Approaches to Biology > Cells at the Nanoscale Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Balaashwin Babu
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida, USA
- Nanoscience Technology Center, University of Central Florida, Orlando, Florida, USA
| | - Shreya Pawar
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida, USA
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA
| | - Agastya Mittal
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida, USA
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA
| | - Elayaraja Kolanthai
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida, USA
| | - Craig J Neal
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida, USA
| | - Melanie Coathup
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida, USA
| | - Sudipta Seal
- Advanced Materials Processing and Analysis Center, Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida, USA
- College of Medicine, Nanoscience Technology Center, University of Central Florida, Orlando, Florida, USA
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17
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Winuprasith T, Koirala P, McClements DJ, Khomein P. Emulsion Technology in Nuclear Medicine: Targeted Radionuclide Therapies, Radiosensitizers, and Imaging Agents. Int J Nanomedicine 2023; 18:4449-4470. [PMID: 37555189 PMCID: PMC10406121 DOI: 10.2147/ijn.s416737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 07/19/2023] [Indexed: 08/10/2023] Open
Abstract
Radiopharmaceuticals serve as a major part of nuclear medicine contributing to both diagnosis and treatment of several diseases, especially cancers. Currently, most radiopharmaceuticals are based on small molecules with targeting ability. However, some concerns over their stability or non-specific interactions leading to off-target localization are among the major challenges that need to be overcome. Emulsion technology has great potential for the fabrication of carrier systems for radiopharmaceuticals. It can be used to create particles with different compositions, structures, sizes, and surface characteristics from a wide range of generally recognized as safe (GRAS) materials, which allows their functionality to be tuned for specific applications. In particular, it is possible to carry out surface modifications to introduce targeting and stealth properties, as well as to control the particle dimensions to manipulate diffusion and penetration properties. Moreover, emulsion preparation methods are usually simple, economic, robust, and scalable, which makes them suitable for medical applications. In this review, we highlight the potential of emulsion technology in nuclear medicine for developing targeted radionuclide therapies, for use as radiosensitizers, and for application in radiotracer delivery in gamma imaging techniques.
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Affiliation(s)
| | - Pankaj Koirala
- Institute of Nutrition, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - David J McClements
- Department of Food Science, University of Massachusetts Amherst, Amherst, MA, 01003, USA
| | - Piyachai Khomein
- Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
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18
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Kumar K, Kumar S, Datta K, Fornace AJ, Suman S. High-LET-Radiation-Induced Persistent DNA Damage Response Signaling and Gastrointestinal Cancer Development. Curr Oncol 2023; 30:5497-5514. [PMID: 37366899 DOI: 10.3390/curroncol30060416] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
Ionizing radiation (IR) dose, dose rate, and linear energy transfer (LET) determine cellular DNA damage quality and quantity. High-LET heavy ions are prevalent in the deep space environment and can deposit a much greater fraction of total energy in a shorter distance within a cell, causing extensive DNA damage relative to the same dose of low-LET photon radiation. Based on the DNA damage tolerance of a cell, cellular responses are initiated for recovery, cell death, senescence, or proliferation, which are determined through a concerted action of signaling networks classified as DNA damage response (DDR) signaling. The IR-induced DDR initiates cell cycle arrest to repair damaged DNA. When DNA damage is beyond the cellular repair capacity, the DDR for cell death is initiated. An alternative DDR-associated anti-proliferative pathway is the onset of cellular senescence with persistent cell cycle arrest, which is primarily a defense mechanism against oncogenesis. Ongoing DNA damage accumulation below the cell death threshold but above the senescence threshold, along with persistent SASP signaling after chronic exposure to space radiation, pose an increased risk of tumorigenesis in the proliferative gastrointestinal (GI) epithelium, where a subset of IR-induced senescent cells can acquire a senescence-associated secretory phenotype (SASP) and potentially drive oncogenic signaling in nearby bystander cells. Moreover, DDR alterations could result in both somatic gene mutations as well as activation of the pro-inflammatory, pro-oncogenic SASP signaling known to accelerate adenoma-to-carcinoma progression during radiation-induced GI cancer development. In this review, we describe the complex interplay between persistent DNA damage, DDR, cellular senescence, and SASP-associated pro-inflammatory oncogenic signaling in the context of GI carcinogenesis.
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Affiliation(s)
- Kamendra Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Santosh Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Kamal Datta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Albert J Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology and Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA
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19
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Zhao L, Tang A, Long F, Mi D, Sun Y. Modeling of ionizing radiation-induced chromosome aberration and tumor prevalence based on two classes of DNA double-strand breaks clustering in chromatin domains. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 259:115038. [PMID: 37229870 DOI: 10.1016/j.ecoenv.2023.115038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/24/2023] [Accepted: 05/17/2023] [Indexed: 05/27/2023]
Abstract
There has been some controversy over the use of radiobiological models when modeling the dose-response curves of ionizing radiation (IR)-induced chromosome aberration and tumor prevalence, as those curves usually show obvious non-targeted effects (NTEs) at low doses of high linear energy transfer (LET) radiation. The lack of understanding the contribution of NTEs to IR-induced carcinogenesis can lead to distinct deviations of relative biological effectiveness (RBE) estimations of carcinogenic potential, which are widely used in radiation risk assessment and radiation protection. In this work, based on the initial pattern of two classes of IR-induced DNA double-strand breaks (DSBs) clustering in chromatin domains and the subsequent incorrect repair processes, we proposed a novel radiobiological model to describe the dose-response curves of two carcinogenic-related endpoints within the same theoretical framework. The representative experimental data was used to verify the consistency and validity of the present model. The fitting results indicated that, compared with targeted effect (TE) and NTE models, the current model has better fitting ability when dealing with the experimental data of chromosome aberration and tumor prevalence induced by multiple types of IR with different LETs. Notably, the present model without introducing an NTE term was adequate to describe the dose-response curves of IR-induced chromosome aberration and tumor prevalence with NTEs in low-dose regions. Based on the fitting parameters, the LET-dependent RBE values were calculated for three given low doses. Our results showed that the RBE values predicted by the current model gradually decrease with the increase of doses for the endpoints of chromosome aberration and tumor prevalence. In addition, the calculated RBE was also compared with those evaluated from other models. These analyses show that the proposed model can be used as an alternative tool to well describe dose-response curves of multiple carcinogenic-related endpoints and effectively estimate RBE in low-dose regions.
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Affiliation(s)
- Lei Zhao
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian 116026, Liaoning, China.
| | - Aiping Tang
- College of Science, Dalian Maritime University, Dalian 116026, Liaoning, China
| | - Fei Long
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian 116026, Liaoning, China
| | - Dong Mi
- College of Science, Dalian Maritime University, Dalian 116026, Liaoning, China.
| | - Yeqing Sun
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian 116026, Liaoning, China.
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Lu Z, Xiao B, Chen W, Tang T, Zhuo Q, Chen X. The potential of ferroptosis combined with radiotherapy in cancer treatment. Front Oncol 2023; 13:1085581. [PMID: 37007068 PMCID: PMC10064444 DOI: 10.3389/fonc.2023.1085581] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/10/2023] [Indexed: 03/19/2023] Open
Abstract
Ferroptosis is a new form of regulatory cell death that is closely related to the balance of redox reactions and the occurrence and development of cancer. There is increasing evidence that inducing ferroptosis in cells has great potential in the treatment of cancer. Especially when combined with traditional therapy, it can improve the sensitivity of cancer cells to traditional therapy and overcome the drug resistance of cancer cells. This paper reviews the signaling pathways regulating ferroptosis and the great potential of ferroptosis and radiotherapy (RT) in cancer treatment and emphasizes the unique therapeutic effects of ferroptosis combined with RT on cancer cells, such as synergy, sensitization and reversal of drug resistance, providing a new direction for cancer treatment. Finally, the challenges and research directions for this joint strategy are discussed.
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Affiliation(s)
- Zekun Lu
- Department of Hepatopancreatobiliary Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Bingkai Xiao
- Department of Hepatopancreatobiliary Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Weibo Chen
- Department of Hepatopancreatobiliary Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Tianyu Tang
- Department of Hepatabiliary Surgery, The Second People’s Hospital of Changshu, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, China
| | - Qifeng Zhuo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xuemin Chen
- Department of Hepatopancreatobiliary Surgery, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- *Correspondence: Xuemin Chen,
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21
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Towards sustainable human space exploration-priorities for radiation research to quantify and mitigate radiation risks. NPJ Microgravity 2023; 9:8. [PMID: 36707520 PMCID: PMC9883222 DOI: 10.1038/s41526-023-00262-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 01/20/2023] [Indexed: 01/28/2023] Open
Abstract
Human spaceflight is entering a new era of sustainable human space exploration. By 2030 humans will regularly fly to the Moon's orbit, return to the Moon's surface and preparations for crewed Mars missions will intensify. In planning these undertakings, several challenges will need to be addressed in order to ensure the safety of astronauts during their space travels. One of the important challenges to overcome, that could be a major showstopper of the space endeavor, is the exposure to the space radiation environment. There is an urgent need for quantifying, managing and limiting the detrimental health risks and electronics damage induced by space radiation exposure. Such risks raise key priority topics for space research programs. Risk limitation involves obtaining a better understanding of space weather phenomena and the complex radiation environment in spaceflight, as well as developing and applying accurate dosimetric instruments, understanding related short- and long-term health risks, and strategies for effective countermeasures to minimize both exposure to space radiation and the remaining effects post exposure. The ESA/SciSpacE Space Radiation White Paper identifies those topics and underlines priorities for future research and development, to enable safe human and robotic exploration of space beyond Low Earth Orbit.
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The 'stealth-bomber' paradigm for deciphering the tumour response to carbon-ion irradiation. Br J Cancer 2023; 128:1429-1438. [PMID: 36639527 PMCID: PMC10070470 DOI: 10.1038/s41416-022-02117-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/01/2022] [Accepted: 12/08/2022] [Indexed: 01/14/2023] Open
Abstract
Numerous studies have demonstrated the higher biological efficacy of carbon-ion irradiation (C-ions) and their ballistic precision compared with photons. At the nanometre scale, the reactive oxygen species (ROS) produced by radiation and responsible for the indirect effects are differentially distributed according to the type of radiation. Photon irradiation induces a homogeneous ROS distribution, whereas ROS remain condensed in clusters in the C-ions tracks. Based on this linear energy transfer-dependent differential nanometric ROS distribution, we propose that the higher biological efficacy and specificities of the molecular response to C-ions rely on a 'stealth-bomber' effect. When biological targets are on the trajectories of the particles, the clustered radicals in the tracks are responsible for a 'bomber' effect. Furthermore, the low proportion of ROS outside the tracks is not able to trigger the cellular mechanisms of defence and proliferation. The ability of C-ions to deceive the cellular defence of the cancer cells is then categorised as a 'stealth' effect. This review aims to classify the biological arguments supporting the paradigm of the 'stealth-bomber' as responsible for the biological superiority of C-ions compared with photons. It also explains how and why C-ions will always be more efficient for treating patients with radioresistant cancers than conventional radiotherapy.
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23
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Huang CY, Lai ZY, Hsu TJ, Chou FI, Liu HM, Chuang YJ. Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses. J Hepatocell Carcinoma 2022; 9:1385-1401. [PMID: 36600987 PMCID: PMC9807134 DOI: 10.2147/jhc.s383959] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 12/04/2022] [Indexed: 12/29/2022] Open
Abstract
Introduction For advanced hepatocellular carcinoma (HCC), resistance to conservative treatments remains a challenge. In previous studies, the therapeutic effectiveness and DNA damage responses of boric acid-mediated boron neutron capture therapy (BA-BNCT) in HCC have been demonstrated in animal models and HCC cell line. On the other hand, numerous studies have shown that high linear energy transfer (LET) radiation can overcome tumor resistance. Since BNCT yields a mixture of high and low LET radiation, we aimed to explore whether and how BA-BNCT could eliminate radioresistant HCC cells. Methods Radioresistant human HCC (HepG2-R) cells were established from HepG2 cells via intermittent irradiation. HepG2 and HepG2-R cells were then irradiated with either γ-ray or neutron radiation of BA-BNCT. Colony formation assays were used to assess cell survival and the relative biological effectiveness (RBE). The expression of phosphorylated H2AX (γH2AX) was also examined by immunocytochemistry and Western blot assays to evaluate the extent of DNA double-strand breaks (DSBs). Finally, the expression levels of DNA damage response-associated proteins were determined, followed by cell cycle analysis and caspase-3 activity analysis. Results Our data demonstrated that under the same dose by γ-ray, BNCT effectively eliminated radioresistant HCC by increasing the number of DNA DSBs (p < 0.05) and impeding their repair (p < 0.05), which verified the high RBE of BNCT. We also found that BNCT resulted in delayed homologous recombination (HR) and inhibited the nonhomologous end-joining (NHEJ) pathway during DNA repair. Markedly, BNCT increased cell arrest (p < 0.05) in the G2/M phase by altering G2 checkpoint signaling and increased PUMA-mediated apoptosis (p < 0.05). Conclusion Our data suggest that DNA damage and repair responses could affect the anticancer efficiency of BNCT in radioresistant HepG2-R cells, which highlights the potential of BNCT as a viable treatment option for recurrent HCC.
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Affiliation(s)
- Chu-Yu Huang
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Zih-Yin Lai
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Tzu-Jung Hsu
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Fong-In Chou
- Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Hong-Ming Liu
- Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Yung-Jen Chuang
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan,Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan,Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan,Correspondence: Yung-Jen Chuang, School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan, Tel +886-3-5742764, Fax +886-3-5715934, Email
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24
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Du TQ, Liu R, Zhang Q, Luo H, Chen Y, Tan M, Wang Q, Wu X, Liu Z, Sun S, Yang K, Tian J, Wang X. Does particle radiation have superior radiobiological advantages for prostate cancer cells? A systematic review of in vitro studies. Eur J Med Res 2022; 27:306. [PMID: 36572945 PMCID: PMC9793637 DOI: 10.1186/s40001-022-00942-2] [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: 09/21/2022] [Accepted: 12/07/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Charged particle beams from protons to carbon ions provide many significant physical benefits in radiation therapy. However, preclinical studies of charged particle therapy for prostate cancer are extremely limited. The aim of this study was to comprehensively investigate the biological effects of charged particles on prostate cancer from the perspective of in vitro studies. METHODS We conducted a systematic review by searching EMBASE (OVID), Medline (OVID), and Web of Science databases to identify the publications assessing the radiobiological effects of charged particle irradiation on prostate cancer cells. The data of relative biological effectiveness (RBE), surviving fraction (SF), standard enhancement ratio (SER) and oxygen enhancement ratio (OER) were extracted. RESULTS We found 12 studies met the eligible criteria. The relative biological effectiveness values of proton and carbon ion irradiation ranged from 0.94 to 1.52, and 1.67 to 3.7, respectively. Surviving fraction of 2 Gy were 0.17 ± 0.12, 0.55 ± 0.20 and 0.53 ± 0.16 in carbon ion, proton, and photon irradiation, respectively. PNKP inhibitor and gold nanoparticles were favorable sensitizing agents, while it was presented poorer performance in GANT61. The oxygen enhancement ratio values of photon and carbon ion irradiation were 2.32 ± 0.04, and 1.77 ± 0.13, respectively. Charged particle irradiation induced more G0-/G1- or G2-/M-phase arrest, more expression of γ-H2AX, more apoptosis, and lower motility and/or migration ability than photon irradiation. CONCLUSIONS Both carbon ion and proton irradiation have advantages over photon irradiation in radiobiological effects on prostate cancer cell lines. Carbon ion irradiation seems to have further advantages over proton irradiation.
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Affiliation(s)
- Tian-Qi Du
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu People’s Republic of China
| | - Ruifeng Liu
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.410726.60000 0004 1797 8419Graduate School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China ,Heavy Ion Therapy Center, Lanzhou Heavy Ion Hospital, Lanzhou, Gansu People’s Republic of China
| | - Qiuning Zhang
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.410726.60000 0004 1797 8419Graduate School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China ,Heavy Ion Therapy Center, Lanzhou Heavy Ion Hospital, Lanzhou, Gansu People’s Republic of China
| | - Hongtao Luo
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.410726.60000 0004 1797 8419Graduate School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China ,Heavy Ion Therapy Center, Lanzhou Heavy Ion Hospital, Lanzhou, Gansu People’s Republic of China
| | - Yanliang Chen
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu People’s Republic of China
| | - Mingyu Tan
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu People’s Republic of China
| | - Qian Wang
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu People’s Republic of China
| | - Xun Wu
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu People’s Republic of China
| | - Zhiqiang Liu
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.410726.60000 0004 1797 8419Graduate School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China ,Heavy Ion Therapy Center, Lanzhou Heavy Ion Hospital, Lanzhou, Gansu People’s Republic of China
| | - Shilong Sun
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.410726.60000 0004 1797 8419Graduate School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China ,Heavy Ion Therapy Center, Lanzhou Heavy Ion Hospital, Lanzhou, Gansu People’s Republic of China
| | - Kehu Yang
- grid.32566.340000 0000 8571 0482Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu People’s Republic of China
| | - Jinhui Tian
- grid.32566.340000 0000 8571 0482Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu People’s Republic of China
| | - Xiaohu Wang
- grid.9227.e0000000119573309Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang Rd, Lanzhou, 730000 Gansu People’s Republic of China ,grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu People’s Republic of China ,grid.410726.60000 0004 1797 8419Graduate School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China ,Heavy Ion Therapy Center, Lanzhou Heavy Ion Hospital, Lanzhou, Gansu People’s Republic of China
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Hao Y, Lu L, Liu A, Lin X, Xiao L, Kong X, Li K, Liang F, Xiong J, Qu L, Li Y, Li J. Integrating bioinformatic strategies in spatial life science research. Brief Bioinform 2022; 23:bbac415. [PMID: 36198665 PMCID: PMC9677476 DOI: 10.1093/bib/bbac415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/15/2022] [Accepted: 08/27/2022] [Indexed: 12/14/2022] Open
Abstract
As space exploration programs progress, manned space missions will become more frequent and farther away from Earth, putting a greater emphasis on astronaut health. Through the collaborative efforts of researchers from various countries, the effect of the space environment factors on living systems is gradually being uncovered. Although a large number of interconnected research findings have been produced, their connection seems to be confused, and many unknown effects are left to be discovered. Simultaneously, several valuable data resources have emerged, accumulating data measuring biological effects in space that can be used to further investigate the unknown biological adaptations. In this review, the previous findings and their correlations are sorted out to facilitate the understanding of biological adaptations to space and the design of countermeasures. The biological effect measurement methods/data types are also organized to provide references for experimental design and data analysis. To aid deeper exploration of the data resources, we summarized common characteristics of the data generated from longitudinal experiments, outlined challenges or caveats in data analysis and provided corresponding solutions by recommending bioinformatics strategies and available models/tools.
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Affiliation(s)
- Yangyang Hao
- Key Laboratory of DGHD, MOE, School of Life Science and Technology, Southeast University, Nanjing, China
| | - Liang Lu
- The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, China
| | - Anna Liu
- Key Laboratory of DGHD, MOE, School of Life Science and Technology, Southeast University, Nanjing, China
| | - Xue Lin
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Li Xiao
- The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, China
| | - Xiaoyue Kong
- Key Laboratory of DGHD, MOE, School of Life Science and Technology, Southeast University, Nanjing, China
| | - Kai Li
- The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, China
| | - Fengji Liang
- The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, China
| | - Jianghui Xiong
- The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, China
| | - Lina Qu
- The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, China
| | - Yinghui Li
- The State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, No. 26 Beiqing Road, Haidian District, Beijing, 100094, China
| | - Jian Li
- Key Laboratory of DGHD, MOE, School of Life Science and Technology, Southeast University, Nanjing, China
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26
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Fathy MM, Saad OA, Elshemey WM, Fahmy HM. Dose-enhancement of MCF 7 cell line radiotherapy using silica-iron oxide nanocomposite. Biochem Biophys Res Commun 2022; 632:100-106. [PMID: 36206593 DOI: 10.1016/j.bbrc.2022.09.087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 09/10/2022] [Accepted: 09/22/2022] [Indexed: 11/25/2022]
Abstract
Cancer radiotherapy is one of the most effective regimens of cancer treatments, but cancer cell radioresistance remains a concern. Radiosensitizers can selectively improve the efficacy of radiotherapy and reduce inherent damage. The purpose of this work is to evaluate the effect of silica-coated iron oxide magnetic nanoparticles (SIONPs) as a radiosensitizer and compare their therapeutic effect with that of Iron oxide magnetic nanoparticles (IONPs). IONPs and SIONPs were characterized using several physical techniques such as a transmission electron microscope (TEM) and Vibrating sample magnetometer (VSM). MTT and DNA double-strand breaks (Comet) assays have been used to detect the cytotoxicity, cell viability, and DNA damage of MCF-7 cells, which were treated with different concentrations of prepared nanoparticles and exposed to an X-ray beam. In this study, an efficient radiosensitizer, SIONPs, was successfully prepared and characterized. With 0.5 Gy dose, dose enhancement factor (DEF) values of cells treated with 5 and 10 μg/ml of IONPs were 1 and 1.09, respectively, while those treated with SIONPs at these concentrations had DEF of 1.21 and 1.32, respectively. Results demonstrated that SIONPs provide a potential for improving the radiosensitivity of breast cancer.
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27
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Huff JL, Plante I, Blattnig SR, Norman RB, Little MP, Khera A, Simonsen LC, Patel ZS. Cardiovascular Disease Risk Modeling for Astronauts: Making the Leap From Earth to Space. Front Cardiovasc Med 2022; 9:873597. [PMID: 35665268 PMCID: PMC9161032 DOI: 10.3389/fcvm.2022.873597] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/26/2022] [Indexed: 11/24/2022] Open
Abstract
NASA has recently completed several long-duration missions to the International Space Station and is solidifying plans to return to the Moon, with an eye toward Mars and beyond. As NASA pushes the boundaries of human space exploration, the hazards of spaceflight, including space radiation, levy an increasing burden on astronaut health and performance. The cardiovascular system may be especially vulnerable due to the combined impacts of space radiation exposure, lack of gravity, and other spaceflight hazards. On Earth, the risk for cardiovascular disease (CVD) following moderate to high radiation doses is well-established from clinical, environmental, and occupational exposures (largely from gamma- and x-rays). Less is known about CVD risks associated with high-energy charged ions found in space and increasingly used in radiotherapy applications on Earth, making this a critical area of investigation for occupational radiation protection. Assessing CVD risk is complicated by its multifactorial nature, where an individual's risk is strongly influenced by factors such as family history, blood pressure, and lipid profiles. These known risk factors provide the basis for development of a variety of clinical risk prediction models (CPMs) that inform the likelihood of medical outcomes over a defined period. These tools improve clinical decision-making, personalize care, and support primary prevention of CVD. They may also be useful for individualizing risk estimates for CVD following radiation exposure both in the clinic and in space. In this review, we summarize unique aspects of radiation risk assessment for astronauts, and we evaluate the most widely used CVD CPMs for their use in NASA radiation risk assessment applications. We describe a comprehensive dual-use risk assessment framework that supports both clinical care and operational management of space radiation health risks using quantitative metrics. This approach is a first step in using personalized medicine for radiation risk assessment to support safe and productive spaceflight and long-term quality of life for NASA astronauts.
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Affiliation(s)
- Janice L. Huff
- National Aeronautics and Space Administration, Langley Research Center, Hampton, VA, United States
- *Correspondence: Janice L. Huff
| | - Ianik Plante
- KBR, Houston, TX, United States
- National Aeronautics and Space Administration, Johnson Space Center, Houston, TX, United States
| | - Steve R. Blattnig
- National Aeronautics and Space Administration, Langley Research Center, Hampton, VA, United States
| | - Ryan B. Norman
- National Aeronautics and Space Administration, Langley Research Center, Hampton, VA, United States
| | - Mark P. Little
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services (DHHS), Radiation Epidemiology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Amit Khera
- Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Lisa C. Simonsen
- National Aeronautics and Space Administration, NASA Headquarters, Washington, DC, United States
| | - Zarana S. Patel
- KBR, Houston, TX, United States
- National Aeronautics and Space Administration, Johnson Space Center, Houston, TX, United States
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Cucinotta FA. Flying without a Net: Space Radiation Cancer Risk Predictions without a Gamma-ray Basis. Int J Mol Sci 2022; 23:4324. [PMID: 35457139 PMCID: PMC9029417 DOI: 10.3390/ijms23084324] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/06/2022] [Accepted: 04/12/2022] [Indexed: 11/24/2022] Open
Abstract
The biological effects of high linear energy transfer (LET) radiation show both a qualitative and quantitative difference when compared to low-LET radiation. However, models used to estimate risks ignore qualitative differences and involve extensive use of gamma-ray data, including low-LET radiation epidemiology, quality factors (QF), and dose and dose-rate effectiveness factors (DDREF). We consider a risk prediction that avoids gamma-ray data by formulating a track structure model of excess relative risk (ERR) with parameters estimated from animal studies using high-LET radiation. The ERR model is applied with U.S. population cancer data to predict lifetime risks to astronauts. Results for male liver and female breast cancer risk show that the ERR model agrees fairly well with estimates of a QF model on non-targeted effects (NTE) and is about 2-fold higher than the QF model that ignores NTE. For male or female lung cancer risk, the ERR model predicts about a 3-fold and more than 7-fold lower risk compared to the QF models with or without NTE, respectively. We suggest a relative risk approach coupled with improved models of tissue-specific cancers should be pursued to reduce uncertainties in space radiation risk projections. This approach would avoid low-LET uncertainties, while including qualitive effects specific to high-LET radiation.
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Affiliation(s)
- Francis A Cucinotta
- Department of Health Physics and Diagnostic Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
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29
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Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair. Expert Rev Mol Med 2022; 24:e15. [PMID: 35357290 DOI: 10.1017/erm.2022.6] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α-particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose.
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Race and ethnic group dependent space radiation cancer risk predictions. Sci Rep 2022; 12:2028. [PMID: 35132138 PMCID: PMC8821552 DOI: 10.1038/s41598-022-06105-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/18/2022] [Indexed: 12/22/2022] Open
Abstract
Future space missions by national space agencies and private industry, including space tourism, will include a diverse makeup of crewmembers with extensive variability in age, sex, and race or ethnic groups. The relative risk (RR) model is used to transfer epidemiology data between populations to estimate radiation risks. In the RR model cancer risk is assumed to be proportional to background cancer rates and limited by other causes of death, which are dependent on genetic, environmental and dietary factors that are population dependent. Here we apply the NSCR-2020 model to make the first predictions of age dependent space radiation cancer risks for several U.S. populations, which includes Asian-Pacific Islanders (API), Black, Hispanic (white and black), and White (non-Hispanic) populations. Results suggest that male API and Hispanic populations have the overall lowest cancer risks, while White females have the highest risk. Blacks have similar total cancer rates than Whites, however their reduced life expectancy leads to modestly lower lifetime radiation risks compared to Whites. There are diverse tissue specific cancer risk ranking across sex and race, which include sex specific organ risks, female’s having larger lung, stomach, and urinary-bladder radiation risks, and male’s having larger colon and brain risks.
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Cote B, Elbarbry F, Bui F, Su JW, Seo K, Nguyen A, Lee M, Rao DA. Mechanistic Basis for the Role of Phytochemicals in Inflammation-Associated Chronic Diseases. Molecules 2022; 27:molecules27030781. [PMID: 35164043 PMCID: PMC8838908 DOI: 10.3390/molecules27030781] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/14/2022] [Accepted: 01/21/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic inflammatory diseases occur in a large portion of the population and are associated with a poor diet. Key natural products found in fruits and vegetables may assist in lowering inflammation associated with chronic diseases such as obesity, diabetes, cardiovascular diseases, and cancer. This review seeks to examine the roles of several natural products, resveratrol (RES), quercetin (QUE), curcumin (CUR), piperine (PIP), epigallocatechin gallate (EGCG), and gingerol (GIN), in their ability to attenuate inflammatory markers in specific diseases states. Additionally, we will discuss findings in past and ongoing clinical trials, detail possible phytochemical–drug interactions, and provide a brief resource for researchers and healthcare professionals on natural product and supplement regulation as well as names of databases with information on efficacy, indications, and natural product–drug interactions. As diet and over-the-counter supplement use are modifiable factors and patients are interested in using complementary and alternative therapies, understanding the mechanisms by which natural products have demonstrated efficacy and the types of drugs they interact with and knowing where to find information on herbs and supplements is important for practicing healthcare providers and researchers interested in this field.
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Affiliation(s)
- Brianna Cote
- College of Pharmacy, Oregon State University, Portland, OR 97201, USA;
| | - Fawzy Elbarbry
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Fiona Bui
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Joe W. Su
- School of Pharmacy, West Coast University, Los Angeles, CA 90004, USA;
| | - Karen Seo
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Arthur Nguyen
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Max Lee
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
| | - Deepa A. Rao
- School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA; (F.E.); (F.B.); (K.S.); (A.N.); (M.L.)
- Correspondence:
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Stati G, Passaretta F, Gindraux F, Centurione L, Di Pietro R. The Role of the CREB Protein Family Members and the Related Transcription Factors in Radioresistance Mechanisms. Life (Basel) 2021; 11:1437. [PMID: 34947968 PMCID: PMC8706059 DOI: 10.3390/life11121437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/02/2021] [Accepted: 12/16/2021] [Indexed: 02/05/2023] Open
Abstract
In the framework of space flight, the risk of radiation carcinogenesis is considered a "red" risk due to the high likelihood of occurrence as well as the high potential impact on the quality of life in terms of disease-free survival after space missions. The cyclic AMP response element-binding protein (CREB) is overexpressed both in haematological malignancies and solid tumours and its expression and function are modulated following irradiation. The CREB protein is a transcription factor and member of the CREB/activating transcription factor (ATF) family. As such, it has an essential role in a wide range of cell processes, including cell survival, proliferation, and differentiation. Among the CREB-related nuclear transcription factors, NF-κB and p53 have a relevant role in cell response to ionising radiation. Their expression and function can decide the fate of the cell by choosing between death or survival. The aim of this review was to define the role of the CREB/ATF family members and the related transcription factors in the response to ionising radiation of human haematological malignancies and solid tumours.
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Affiliation(s)
- Gianmarco Stati
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
| | - Francesca Passaretta
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
| | - Florelle Gindraux
- Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, Université Bourgogne Franche-Comté, 25030 Besançon, France;
- Service de Chirurgie Orthopédique, Traumatologique et Plastique, CHU, 25030 Besançon, France
| | - Lucia Centurione
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
| | - Roberta Di Pietro
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.P.); (L.C.); (R.D.P.)
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Komarova LN, Melnikova AA, Baldov DA. Synergetic effects of the combined action of carbon ions and the chemotherapy drug doxorubicin on HeLa cancer cells. NUCLEAR ENERGY AND TECHNOLOGY 2021. [DOI: 10.3897/nucet.7.78336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Proton and carbon beam therapy is currently recognized as the most effective and highly accurate form of radiation therapy for deeply located tumors, including radioresistant ones. This is due to the fact that they have all the advantages of spatial dose distribution and, at the same time, are densely ionizing radiations capable of effectively affecting hypoxic, slow-growing tumors and other neoplasms that are insensitive to traditional types of radiation. It is well known that one of the main methods for treating neoplasms is chemotherapy. The predominant mechanism of action of anti-tumor drugs is the induction of DNA damage with the subsequent impossibility of repair. In our study, we used an anti-tumor antibiotic of the anthracycline series, doxorubicin. The assessment of the potential significance of the synergistic interaction of ionizing radiation with chemical preparations in medical radiology remains an urgent and unresolved problem. It is possible to achieve the maximum effect of the combined action of two agents when they act simultaneously. The phenomenon of synergy can be used to optimize the combined use of radiation and chemotherapy in clinical practice. In this regard, it seems relevant to conduct a study for HeLa cancer cells exposed to ionizing radiation, an antitumor drug, as well as their combination. In the course of the study, results were obtained on the manifestation of the synergistic nature of the agents used, which is of great practical and theoretical importance for understanding the mechanism of the combined effect of ionizing radiation and the chemotherapy drug (doxorubicin). The obtained data can be helpful in optimizing the combined effects in order to achieve maximum synergistic interaction.
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Aranza-Martínez A, Sánchez-Pérez J, Brito-Elias L, López-Camarillo C, Cantú de León D, Pérez-Plasencia C, López-Urrutia E. Non-Coding RNAs Associated With Radioresistance in Triple-Negative Breast Cancer. Front Oncol 2021; 11:752270. [PMID: 34804940 PMCID: PMC8599982 DOI: 10.3389/fonc.2021.752270] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022] Open
Abstract
The resistance that Triple-Negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, develops against radiotherapy is a complex phenomenon involving several regulators of cell metabolism and gene expression; understanding it is the only way to overcome it. We focused this review on the contribution of the two leading classes of regulatory non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), against ionizing radiation-based therapies. We found that these regulatory RNAs are mainly associated with DNA damage response, cell death, and cell cycle regulation, although they regulate other processes like cell signaling and metabolism. Several regulatory RNAs regulate multiple pathways simultaneously, such as miR-139-5p, the miR-15 family, and the lncRNA HOTAIR. On the other hand, proteins such as CHK1 and WEE1 are targeted by several regulatory RNAs simultaneously. Interestingly, the study of miRNA/lncRNA/mRNA regulation axes increases, opening new avenues for understanding radioresistance. Many of the miRNAs and lncRNAs that we reviewed here can be used as molecular markers or targeted by upcoming therapeutic options, undoubtedly contributing to a better prognosis for TNBC patients.
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Affiliation(s)
- Alberto Aranza-Martínez
- Laboratorio de Genómica Funcional, Facultad de Estudios Superiores Iztacala Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, Mexico
| | - Julio Sánchez-Pérez
- Laboratorio de Genómica Funcional, Facultad de Estudios Superiores Iztacala Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, Mexico
| | - Luis Brito-Elias
- Laboratorio de Genómica Funcional, Facultad de Estudios Superiores Iztacala Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico
| | - David Cantú de León
- Dirección de Investigación, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica Funcional, Facultad de Estudios Superiores Iztacala Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, Mexico
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Eduardo López-Urrutia
- Laboratorio de Genómica Funcional, Facultad de Estudios Superiores Iztacala Universidad Nacional Autónoma de México (UNAM), Tlalnepantla, Mexico
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Matar M, Gokoglu SA, Prelich MT, Gallo CA, Iqbal AK, Britten RA, Prabhu RK, Myers JG. Machine Learning Models to Predict Cognitive Impairment of Rodents Subjected to Space Radiation. Front Syst Neurosci 2021; 15:713131. [PMID: 34588962 PMCID: PMC8473791 DOI: 10.3389/fnsys.2021.713131] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/27/2021] [Indexed: 11/13/2022] Open
Abstract
This research uses machine-learned computational analyses to predict the cognitive performance impairment of rats induced by irradiation. The experimental data in the analyses is from a rodent model exposed to ≤15 cGy of individual galactic cosmic radiation (GCR) ions: 4He, 16O, 28Si, 48Ti, or 56Fe, expected for a Lunar or Mars mission. This work investigates rats at a subject-based level and uses performance scores taken before irradiation to predict impairment in attentional set-shifting (ATSET) data post-irradiation. Here, the worst performing rats of the control group define the impairment thresholds based on population analyses via cumulative distribution functions, leading to the labeling of impairment for each subject. A significant finding is the exhibition of a dose-dependent increasing probability of impairment for 1 to 10 cGy of 28Si or 56Fe in the simple discrimination (SD) stage of the ATSET, and for 1 to 10 cGy of 56Fe in the compound discrimination (CD) stage. On a subject-based level, implementing machine learning (ML) classifiers such as the Gaussian naïve Bayes, support vector machine, and artificial neural networks identifies rats that have a higher tendency for impairment after GCR exposure. The algorithms employ the experimental prescreen performance scores as multidimensional input features to predict each rodent's susceptibility to cognitive impairment due to space radiation exposure. The receiver operating characteristic and the precision-recall curves of the ML models show a better prediction of impairment when 56Fe is the ion in question in both SD and CD stages. They, however, do not depict impairment due to 4He in SD and 28Si in CD, suggesting no dose-dependent impairment response in these cases. One key finding of our study is that prescreen performance scores can be used to predict the ATSET performance impairments. This result is significant to crewed space missions as it supports the potential of predicting an astronaut's impairment in a specific task before spaceflight through the implementation of appropriately trained ML tools. Future research can focus on constructing ML ensemble methods to integrate the findings from the methodologies implemented in this study for more robust predictions of cognitive decrements due to space radiation exposure.
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Affiliation(s)
- Mona Matar
- NASA Glenn Research Center, Cleveland, OH, United States
| | | | | | | | - Asad K. Iqbal
- ZIN Technologies, Inc., Cleveland, OH, United States
| | - Richard A. Britten
- Department of Radiation Oncology, Eastern Virginia Medical School, Norfolk, VA, United States
| | - R. K. Prabhu
- Universities Space Research Association, Cleveland, OH, United States
| | - Jerry G. Myers
- NASA Glenn Research Center, Cleveland, OH, United States
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Boyd A, Byrne S, Middleton RJ, Banati RB, Liu GJ. Control of Neuroinflammation through Radiation-Induced Microglial Changes. Cells 2021; 10:2381. [PMID: 34572030 PMCID: PMC8468704 DOI: 10.3390/cells10092381] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/02/2021] [Accepted: 09/02/2021] [Indexed: 12/15/2022] Open
Abstract
Microglia, the innate immune cells of the central nervous system, play a pivotal role in the modulation of neuroinflammation. Neuroinflammation has been implicated in many diseases of the CNS, including Alzheimer's disease and Parkinson's disease. It is well documented that microglial activation, initiated by a variety of stressors, can trigger a potentially destructive neuroinflammatory response via the release of pro-inflammatory molecules, and reactive oxygen and nitrogen species. However, the potential anti-inflammatory and neuroprotective effects that microglia are also thought to exhibit have been under-investigated. The application of ionising radiation at different doses and dose schedules may reveal novel methods for the control of microglial response to stressors, potentially highlighting avenues for treatment of neuroinflammation associated CNS disorders, such as Alzheimer's disease and Parkinson's disease. There remains a need to characterise the response of microglia to radiation, particularly low dose ionising radiation.
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Affiliation(s)
- Alexandra Boyd
- Australian Nuclear Science and Technology Organisation, Sydney, NSW 2234, Australia; (A.B.); (S.B.); (R.J.M.); (R.B.B.)
| | - Sarah Byrne
- Australian Nuclear Science and Technology Organisation, Sydney, NSW 2234, Australia; (A.B.); (S.B.); (R.J.M.); (R.B.B.)
| | - Ryan J. Middleton
- Australian Nuclear Science and Technology Organisation, Sydney, NSW 2234, Australia; (A.B.); (S.B.); (R.J.M.); (R.B.B.)
| | - Richard B. Banati
- Australian Nuclear Science and Technology Organisation, Sydney, NSW 2234, Australia; (A.B.); (S.B.); (R.J.M.); (R.B.B.)
- Discipline of Medical Imaging & Radiation Sciences, Faculty of Medicine and Health, Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia
| | - Guo-Jun Liu
- Australian Nuclear Science and Technology Organisation, Sydney, NSW 2234, Australia; (A.B.); (S.B.); (R.J.M.); (R.B.B.)
- Discipline of Medical Imaging & Radiation Sciences, Faculty of Medicine and Health, Brain and Mind Centre, University of Sydney, Sydney, NSW 2050, Australia
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Bailey SM, Luxton JJ, McKenna MJ, Taylor LE, George KA, Jhavar SG, Swanson GP. Ad Astra - telomeres in space! Int J Radiat Biol 2021; 98:395-403. [PMID: 34270368 DOI: 10.1080/09553002.2021.1956010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE My journey to the stars began as I - along with the whole world - stood still and watched Neil Armstrong take those first small steps on the Moon. Fast forward 50 years and NASA astronauts Scott Kelly and Christina Koch each spend nearly a year in space aboard the International Space Station (ISS), a remarkable multinational collaborative project and floating U.S. National Laboratory that has supported continuous human presence in low Earth orbit for the past 20 years. Marking a new era of human space exploration, the first commercial rocket, SpaceX Falcon 9, recently launched NASA astronauts Doug Hurley and Bob Behnken in the Crew Dragon spacecraft Endeavor to the ISS and returned safely to Earth. NASA and its commercial partners are rapidly advancing innovative space technologies, and with the recently announced Artemis team of astronauts, plans to send the first woman and next man back to the moon and establish sustainable exploration by the end of the decade. Humankind will then be poised to take the next giant leap - pioneering human exploration of Mars. CONCLUSIONS Historically, fewer than 600 individuals have participated in spaceflight, the vast majority of whom have been middle aged males (35-55 years) on short duration missions (less than 20 days). Thus, as the number and diversity of space travelers increase, a better understanding of how long-duration spaceflight affects human health is essential to maintaining individual astronaut performance during, and improving disease and aging trajectories following, future exploration missions. Here, I review findings from our NASA Twins Study and Telomeres investigations, highlighting potential mechanistic roles of chronic space radiation exposure in changes in telomere length and persistent DNA damage responses associated with long-duration spaceflight. Importantly, similar trends were observed in prostate cancer patients undergoing intensity-modulated radiation therapy (IMRT), additional support specifically for the role of radiation exposure. Individual differences in response were also observed in both cohorts, underscoring the importance of developing personalized approaches for evaluating human health effects and long-term outcomes associated with radiation exposures, whether on Earth or living in the extreme environment of space.
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Affiliation(s)
- Susan M Bailey
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.,Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Jared J Luxton
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.,Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Miles J McKenna
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.,Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Lynn E Taylor
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
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Wakayama S, Ito D, Kamada Y, Shimazu T, Suzuki T, Nagamatsu A, Araki R, Ishikawa T, Kamimura S, Hirose N, Kazama K, Yang L, Inoue R, Kikuchi Y, Hayashi E, Emura R, Watanabe R, Nagatomo H, Suzuki H, Yamamori T, Tada MN, Osada I, Umehara M, Sano H, Kasahara H, Higashibata A, Yano S, Abe M, Kishigami S, Kohda T, Ooga M, Wakayama T. Evaluating the long-term effect of space radiation on the reproductive normality of mammalian sperm preserved on the International Space Station. SCIENCE ADVANCES 2021; 7:7/24/eabg5554. [PMID: 34117068 PMCID: PMC8195474 DOI: 10.1126/sciadv.abg5554] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/23/2021] [Indexed: 06/12/2023]
Abstract
Space radiation may cause DNA damage to cells and concern for the inheritance of mutations in offspring after deep space exploration. However, there is no way to study the long-term effects of space radiation using biological materials. Here, we developed a method to evaluate the biological effect of space radiation and examined the reproductive potential of mouse freeze-dried spermatozoa stored on the International Space Station (ISS) for the longest period in biological research. The space radiation did not affect sperm DNA or fertility after preservation on ISS, and many genetically normal offspring were obtained without reducing the success rate compared to the ground-preserved control. The results of ground x-ray experiments showed that sperm can be stored for more than 200 years in space. These results suggest that the effect of deep space radiation on mammalian reproduction can be evaluated using spermatozoa, even without being monitored by astronauts in Gateway.
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Affiliation(s)
- Sayaka Wakayama
- Advanced Biotechnology Center, University of Yamanashi, Yamanashi 400-8510, Japan.
| | - Daiyu Ito
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Yuko Kamada
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Toru Shimazu
- Space Utilization Promotion Department, Japan Space Forum, Tokyo 101-0062, Japan
| | - Tomomi Suzuki
- Japan Aerospace Exploration Agency, Tsukuba 305-8505, Japan
| | - Aiko Nagamatsu
- Japan Aerospace Exploration Agency, Tsukuba 305-8505, Japan
| | - Ryoko Araki
- Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Takahiro Ishikawa
- Department of Accelerator and Medical Physics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Satoshi Kamimura
- Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Naoki Hirose
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Kousuke Kazama
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Li Yang
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Rei Inoue
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Yasuyuki Kikuchi
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Erika Hayashi
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Rina Emura
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Ren Watanabe
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Hiroaki Nagatomo
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Hiromi Suzuki
- Space Utilization Promotion Department, Japan Space Forum, Tokyo 101-0062, Japan
| | - Tohru Yamamori
- Space Utilization Promotion Department, Japan Space Forum, Tokyo 101-0062, Japan
| | - Motoki N Tada
- Japan Manned Space Systems Corporation, Tokyo 100-0004, Japan
| | - Ikuko Osada
- Japan Manned Space Systems Corporation, Tokyo 100-0004, Japan
| | - Masumi Umehara
- Advanced Engineering Services Co. Ltd, Tsukuba, Ibaraki 305-0032, Japan
| | - Hiromi Sano
- Japan Manned Space Systems Corporation, Tokyo 100-0004, Japan
| | - Haruo Kasahara
- Japan Manned Space Systems Corporation, Tokyo 100-0004, Japan
| | | | - Sachiko Yano
- Japan Aerospace Exploration Agency, Tsukuba 305-8505, Japan
| | - Masumi Abe
- Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Satoshi Kishigami
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Takashi Kohda
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Masatoshi Ooga
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
| | - Teruhiko Wakayama
- Advanced Biotechnology Center, University of Yamanashi, Yamanashi 400-8510, Japan.
- Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan
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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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40
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Rad-Bio-App: a discovery environment for biologists to explore spaceflight-related radiation exposures. NPJ Microgravity 2021; 7:15. [PMID: 33976230 PMCID: PMC8113475 DOI: 10.1038/s41526-021-00143-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 03/29/2021] [Indexed: 02/07/2023] Open
Abstract
In addition to microgravity, spaceflight simultaneously exposes biology to a suite of other stimuli. For example, in space, organisms experience ionizing radiation environments that significantly differ in both quality and quantity from those normally experienced on Earth. However, data on radiation exposure during space missions is often complex to access and to understand, limiting progress towards defining how radiation affects organisms against the unique background of spaceflight. To help address this challenge, we have developed the Rad-Bio-App. This web-accessible database imports radiation metadata from experiments archived in NASA’s GeneLab data repository, and then allows the user to explore these experiments both in the context of their radiation exposure and through their other metadata and results. Rad-Bio-App provides an easy-to-use, graphically-driven environment to enable both radiation biologists and non-specialist researchers to visualize, and understand the impact of ionizing radiation on various biological systems in the context of spaceflight.
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Luxton JJ, McKenna MJ, Taylor LE, George KA, Zwart SR, Crucian BE, Drel VR, Garrett-Bakelman FE, Mackay MJ, Butler D, Foox J, Grigorev K, Bezdan D, Meydan C, Smith SM, Sharma K, Mason CE, Bailey SM. Temporal Telomere and DNA Damage Responses in the Space Radiation Environment. Cell Rep 2020; 33:108435. [PMID: 33242411 DOI: 10.1016/j.celrep.2020.108435] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/15/2020] [Accepted: 11/04/2020] [Indexed: 02/08/2023] Open
Abstract
Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration's (NASA's) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.
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Affiliation(s)
- Jared J Luxton
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Miles J McKenna
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Lynn E Taylor
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | | | - Sara R Zwart
- University of Texas Medical Branch, Galveston, TX, USA
| | | | - Viktor R Drel
- Center for Renal Precision Medicine, UT Health, San Antonio, TX, USA
| | - Francine E Garrett-Bakelman
- Department of Medicine, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, University of Virginia, Charlottesville, VA, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
| | - Matthew J Mackay
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Daniel Butler
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Jonathan Foox
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Kirill Grigorev
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Daniela Bezdan
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Cem Meydan
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | | | - Kumar Sharma
- Center for Renal Precision Medicine, UT Health, San Antonio, TX, USA
| | - Christopher E Mason
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
| | - Susan M Bailey
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA.
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Luxton JJ, McKenna MJ, Lewis A, Taylor LE, George KA, Dixit SM, Moniz M, Benegas W, Mackay MJ, Mozsary C, Butler D, Bezdan D, Meydan C, Crucian BE, Zwart SR, Smith SM, Mason CE, Bailey SM. Telomere Length Dynamics and DNA Damage Responses Associated with Long-Duration Spaceflight. Cell Rep 2020; 33:108457. [PMID: 33242406 DOI: 10.1016/j.celrep.2020.108457] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/31/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Telomere length dynamics and DNA damage responses were assessed before, during, and after one-year or shorter duration missions aboard the International Space Station (ISS) in a comparatively large cohort of astronauts (n = 11). Although generally healthy individuals, astronauts tended to have significantly shorter telomeres and lower telomerase activity than age- and sex-matched ground controls before and after spaceflight. Although telomeres were longer during spaceflight irrespective of mission duration, telomere length shortened rapidly upon return to Earth, and overall astronauts had shorter telomeres after spaceflight than they did before; inter-individual differences were identified. During spaceflight, all crewmembers experienced oxidative stress, which positively correlated with telomere length dynamics. Significantly increased frequencies of chromosomal inversions were observed during and after spaceflight; changes in cell populations were also detected. We propose a telomeric adaptive response to chronic oxidative damage in extreme environments, whereby the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway is transiently activated in normal somatic cells.
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Affiliation(s)
- Jared J Luxton
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Miles J McKenna
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Aidan Lewis
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Lynn E Taylor
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | | | - Sameer M Dixit
- Center for Molecular Dynamics - Nepal (CMDN), Kathmandu, Nepal
| | | | | | - Matthew J Mackay
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Christopher Mozsary
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Daniel Butler
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Daniela Bezdan
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Cem Meydan
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA
| | - Brian E Crucian
- Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, USA
| | - Sara R Zwart
- University of Texas Medical Branch, Galveston, TX, USA
| | - Scott M Smith
- Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, USA
| | - Christopher E Mason
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
| | - Susan M Bailey
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA.
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Afshinnekoo E, Scott RT, MacKay MJ, Pariset E, Cekanaviciute E, Barker R, Gilroy S, Hassane D, Smith SM, Zwart SR, Nelman-Gonzalez M, Crucian BE, Ponomarev SA, Orlov OI, Shiba D, Muratani M, Yamamoto M, Richards SE, Vaishampayan PA, Meydan C, Foox J, Myrrhe J, Istasse E, Singh N, Venkateswaran K, Keune JA, Ray HE, Basner M, Miller J, Vitaterna MH, Taylor DM, Wallace D, Rubins K, Bailey SM, Grabham P, Costes SV, Mason CE, Beheshti A. Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration. Cell 2020; 183:1162-1184. [PMID: 33242416 PMCID: PMC8441988 DOI: 10.1016/j.cell.2020.10.050] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022]
Abstract
Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.
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Affiliation(s)
- Ebrahim Afshinnekoo
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ryan T Scott
- KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Matthew J MacKay
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10021, USA
| | - Eloise Pariset
- Universities Space Research Association (USRA), Mountain View, CA 94043, USA; Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Egle Cekanaviciute
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Richard Barker
- Department of Botany, University of Wisconsin, Madison, WI 53706, USA
| | - Simon Gilroy
- Department of Botany, University of Wisconsin, Madison, WI 53706, USA
| | | | - Scott M Smith
- Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX 77058, USA
| | - Sara R Zwart
- Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Mayra Nelman-Gonzalez
- KBR, Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX 77058, USA
| | - Brian E Crucian
- Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX 77058, USA
| | - Sergey A Ponomarev
- Institute for the Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia
| | - Oleg I Orlov
- Institute for the Biomedical Problems, Russian Academy of Sciences, 123007 Moscow, Russia
| | - Dai Shiba
- JEM Utilization Center, Human Spaceflight Technology Directorate, Japan Aerospace Exploration Agency (JAXA), Ibaraki 305-8505, Japan
| | - Masafumi Muratani
- Transborder Medical Research Center, and Department of Genome Biology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573, Japan
| | - Stephanie E Richards
- Bionetics, NASA Kennedy Space Center, Kennedy Space Center, Merritt Island, FL 32899, USA
| | - Parag A Vaishampayan
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Cem Meydan
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jonathan Foox
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jacqueline Myrrhe
- European Space Agency, Research and Payloads Group, Data Exploitation and Utilisation Strategy Office, 2200 AG Noordwijk, the Netherlands
| | - Eric Istasse
- European Space Agency, Research and Payloads Group, Data Exploitation and Utilisation Strategy Office, 2200 AG Noordwijk, the Netherlands
| | - Nitin Singh
- Biotechnology and Planetary Protection Group, Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109, USA
| | - Kasthuri Venkateswaran
- Biotechnology and Planetary Protection Group, Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109, USA
| | - Jessica A Keune
- Space Medicine Operations Division, NASA Johnson Space Center, Houston, TX 77058, USA
| | - Hami E Ray
- ASRC Federal Space and Defense, Inc., Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA
| | - Mathias Basner
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jack Miller
- KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Martha Hotz Vitaterna
- Center for Sleep and Circadian Biology, Northwestern University, Evanston, IL 60208, USA; Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA
| | - Deanne M Taylor
- Department of Biomedical Informatics, The Children's Hospital of Philadelphia, PA 19104, USA; Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Douglas Wallace
- Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kathleen Rubins
- Astronaut Office, NASA Johnson Space Center, Houston, TX 77058, USA
| | - Susan M Bailey
- Department of Environmental & Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
| | - Peter Grabham
- Center for Radiological Research, Department of Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10027, USA.
| | - Sylvain V Costes
- Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA.
| | - Christopher E Mason
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10021, USA; The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, NY 10021, USA.
| | - Afshin Beheshti
- KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94035, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Patel ZS, Brunstetter TJ, Tarver WJ, Whitmire AM, Zwart SR, Smith SM, Huff JL. Red risks for a journey to the red planet: The highest priority human health risks for a mission to Mars. NPJ Microgravity 2020; 6:33. [PMID: 33298950 PMCID: PMC7645687 DOI: 10.1038/s41526-020-00124-6] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/30/2020] [Indexed: 12/19/2022] Open
Abstract
NASA's plans for space exploration include a return to the Moon to stay-boots back on the lunar surface with an orbital outpost. This station will be a launch point for voyages to destinations further away in our solar system, including journeys to the red planet Mars. To ensure success of these missions, health and performance risks associated with the unique hazards of spaceflight must be adequately controlled. These hazards-space radiation, altered gravity fields, isolation and confinement, closed environments, and distance from Earth-are linked with over 30 human health risks as documented by NASA's Human Research Program. The programmatic goal is to develop the tools and technologies to adequately mitigate, control, or accept these risks. The risks ranked as "red" have the highest priority based on both the likelihood of occurrence and the severity of their impact on human health, performance in mission, and long-term quality of life. These include: (1) space radiation health effects of cancer, cardiovascular disease, and cognitive decrements (2) Spaceflight-Associated Neuro-ocular Syndrome (3) behavioral health and performance decrements, and (4) inadequate food and nutrition. Evaluation of the hazards and risks in terms of the space exposome-the total sum of spaceflight and lifetime exposures and how they relate to genetics and determine the whole-body outcome-will provide a comprehensive picture of risk profiles for individual astronauts. In this review, we provide a primer on these "red" risks for the research community. The aim is to inform the development of studies and projects with high potential for generating both new knowledge and technologies to assist with mitigating multisystem risks to crew health during exploratory missions.
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Affiliation(s)
- Zarana S Patel
- KBR, Houston, TX, USA.
- NASA Lyndon B. Johnson Space Center, Houston, TX, USA.
| | | | | | | | - Sara R Zwart
- NASA Lyndon B. Johnson Space Center, Houston, TX, USA
- University of Texas Medical Branch at Galveston, Galveston, TX, USA
| | - Scott M Smith
- NASA Lyndon B. Johnson Space Center, Houston, TX, USA
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Zhang S, Wimmer-Schweingruber RF, Yu J, Wang C, Fu Q, Zou Y, Sun Y, Wang C, Hou D, Böttcher SI, Burmeister S, Seimetz L, Schuster B, Knierim V, Shen G, Yuan B, Lohf H, Guo J, Xu Z, Freiherr von Forstner JL, Kulkarni SR, Xu H, Xue C, Li J, Zhang Z, Zhang H, Berger T, Matthiä D, Hellweg CE, Hou X, Cao J, Chang Z, Zhang B, Chen Y, Geng H, Quan Z. First measurements of the radiation dose on the lunar surface. SCIENCE ADVANCES 2020; 6:eaaz1334. [PMID: 32978156 PMCID: PMC7518862 DOI: 10.1126/sciadv.aaz1334] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 08/12/2020] [Indexed: 05/21/2023]
Abstract
Human exploration of the Moon is associated with substantial risks to astronauts from space radiation. On the surface of the Moon, this consists of the chronic exposure to galactic cosmic rays and sporadic solar particle events. The interaction of this radiation field with the lunar soil leads to a third component that consists of neutral particles, i.e., neutrons and gamma radiation. The Lunar Lander Neutrons and Dosimetry experiment aboard China's Chang'E 4 lander has made the first ever measurements of the radiation exposure to both charged and neutral particles on the lunar surface. We measured an average total absorbed dose rate in silicon of 13.2 ± 1 μGy/hour and a neutral particle dose rate of 3.1 ± 0.5 μGy/hour.
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Affiliation(s)
- Shenyi Zhang
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- University of Chinese Academy of Science, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Robert F Wimmer-Schweingruber
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China.
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Jia Yu
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Chi Wang
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
| | - Qiang Fu
- National Astronomical Observatories, Chinese Academy of Sciences, Beijing, PR China
- Key Laboratory of Lunar and Deep Space Exploration, Chinese Academy of Sciences, Beijing, PR China
| | - Yongliao Zou
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
| | - Yueqiang Sun
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Chunqin Wang
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Donghui Hou
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- University of Chinese Academy of Science, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Stephan I Böttcher
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Sönke Burmeister
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Lars Seimetz
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Björn Schuster
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Violetta Knierim
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Guohong Shen
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Bin Yuan
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Henning Lohf
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Jingnan Guo
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
- University of Science and Technology of China, Hefei, PR China
- CAS Center for Excellence in Comparative Planetology, Hefei, PR China
| | - Zigong Xu
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | | | - Shrinivasrao R Kulkarni
- Institute of Experimental and Applied Physics, Christian-Albrechts-University, Kiel, Germany
| | - Haitao Xu
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
| | - Changbin Xue
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
| | - Jun Li
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
| | - Zhe Zhang
- Lunar Exploration and Space Engineering Center, Beijing, PR China
| | - He Zhang
- China Academy of Space Technology, Beijing, PR China
| | - Thomas Berger
- German Aerospace Center (DLR), Institute of Aerospace Medicine, Cologne, Germany
| | - Daniel Matthiä
- German Aerospace Center (DLR), Institute of Aerospace Medicine, Cologne, Germany
| | - Christine E Hellweg
- German Aerospace Center (DLR), Institute of Aerospace Medicine, Cologne, Germany
| | - Xufeng Hou
- 18th Research Institute, China Electronics Technology Group Corporation, Tianjin, PR China
| | | | - Zhen Chang
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Binquan Zhang
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
| | - Yuesong Chen
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
| | - Hao Geng
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
| | - Zida Quan
- National Space Science Center, Chinese Academy of Sciences, Beijing, PR China
- Beijing Key Laboratory of Space Environment Exploration, Beijing, PR China
- Key Laboratory of Environmental Space Situation Awareness Technology, Beijing, PR China
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The Determinant of DNA Repair Pathway Choices in Ionising Radiation-Induced DNA Double-Strand Breaks. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4834965. [PMID: 32908893 PMCID: PMC7468606 DOI: 10.1155/2020/4834965] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/13/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023]
Abstract
Ionising radiation- (IR-) induced DNA double-strand breaks (DSBs) are considered to be the deleterious DNA lesions that pose a serious threat to genomic stability. The major DNA repair pathways, including classical nonhomologous end joining, homologous recombination, single-strand annealing, and alternative end joining, play critical roles in countering and eliciting IR-induced DSBs to ensure genome integrity. If the IR-induced DNA DSBs are not repaired correctly, the residual or incorrectly repaired DSBs can result in genomic instability that is associated with certain human diseases. Although many efforts have been made in investigating the major mechanisms of IR-induced DNA DSB repair, it is still unclear what determines the choices of IR-induced DNA DSB repair pathways. In this review, we discuss how the mechanisms of IR-induced DSB repair pathway choices can operate in irradiated cells. We first briefly describe the main mechanisms of the major DNA DSB repair pathways and the related key repair proteins. Based on our understanding of the characteristics of IR-induced DNA DSBs and the regulatory mechanisms of DSB repair pathways in irradiated cells and recent advances in this field, We then highlight the main factors and associated challenges to determine the IR-induced DSB repair pathway choices. We conclude that the type and distribution of IR-induced DSBs, chromatin state, DNA-end structure, and DNA-end resection are the main determinants of the choice of the IR-induced DNA DSB repair pathway.
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Zhao L, Bao C, Shang Y, He X, Ma C, Lei X, Mi D, Sun Y. The Determinant of DNA Repair Pathway Choices in Ionising Radiation-Induced DNA Double-Strand Breaks. BIOMED RESEARCH INTERNATIONAL 2020. [DOI: doi.org/10.1155/2020/4834965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Ionising radiation- (IR-) induced DNA double-strand breaks (DSBs) are considered to be the deleterious DNA lesions that pose a serious threat to genomic stability. The major DNA repair pathways, including classical nonhomologous end joining, homologous recombination, single-strand annealing, and alternative end joining, play critical roles in countering and eliciting IR-induced DSBs to ensure genome integrity. If the IR-induced DNA DSBs are not repaired correctly, the residual or incorrectly repaired DSBs can result in genomic instability that is associated with certain human diseases. Although many efforts have been made in investigating the major mechanisms of IR-induced DNA DSB repair, it is still unclear what determines the choices of IR-induced DNA DSB repair pathways. In this review, we discuss how the mechanisms of IR-induced DSB repair pathway choices can operate in irradiated cells. We first briefly describe the main mechanisms of the major DNA DSB repair pathways and the related key repair proteins. Based on our understanding of the characteristics of IR-induced DNA DSBs and the regulatory mechanisms of DSB repair pathways in irradiated cells and recent advances in this field, We then highlight the main factors and associated challenges to determine the IR-induced DSB repair pathway choices. We conclude that the type and distribution of IR-induced DSBs, chromatin state, DNA-end structure, and DNA-end resection are the main determinants of the choice of the IR-induced DNA DSB repair pathway.
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Affiliation(s)
- Lei Zhao
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian, 116026 Liaoning, China
| | - Chengyu Bao
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian, 116026 Liaoning, China
| | - Yuxuan Shang
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian, 116026 Liaoning, China
| | - Xinye He
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian, 116026 Liaoning, China
| | - Chiyuan Ma
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Xiaohua Lei
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Dong Mi
- College of Science, Dalian Maritime University, Dalian, Liaoning, China
| | - Yeqing Sun
- Institute of Environmental Systems Biology, College of Environmental Science and Engineering, Dalian Maritime University, Dalian, 116026 Liaoning, China
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Wang C, An Y, Wang Y, Shen K, Wang X, Luan W, Ma F, Ni L, Liu M, Yu L. Insulin-like growth factor-I activates NFκB and NLRP3 inflammatory signalling via ROS in cancer cells. Mol Cell Probes 2020; 52:101583. [PMID: 32360740 DOI: 10.1016/j.mcp.2020.101583] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 12/17/2022]
Abstract
Previous studies have demonstrated that insulin-like growth factor-I (IGF-1) and reactive oxygen species (ROS) are involved in the development and progression of various cancers. However, their regulatory mechanism remains unknown. In this study, we treated cancer cells (HeLa, HepG2 and SW1116 cells) and normal cells (NCM-460) with IGF-1 at different concentrations and for different times and found that cancer cells produced large amounts of cytoplasmic ROS in cancer cells but not in normal cells. Further mechanistic analysis demonstrated that IGF-1 activated NFκB and NLRP3 inflammatory signalling in HeLa cells; systematic analysis indicated that IGF-1 activates NFκB and NLRP3, and the activation was cytosolic ROS- and NADPH oxidase 2 (NOX2)-dependent. Additionally, through coimmunoprecipitation experiments, we found that the IRS-1/COX2/mPGES-1/MAPKs/RAC2/NOX2 pathway nexus was involved in IGF-1-induced NFκB and NLRP3 production. Finally, we validated the regulatory mechanisms through IRS-1, mPGES-1 or NOX2 inhibition using their respective selective inhibitors or shRNA knockdown. Taken together, this is the first report on the mechanism by which IGF-1 activates NFκB and NLRP3 inflammatory signalling via ROS. These findings pave the way for an in-depth study of the role of IGF-1 and ROS in inflammation associated with the development and progression of cancer.
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Affiliation(s)
- Chao Wang
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Yanan An
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Yang Wang
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Keshu Shen
- Jilin Hepatobiliary Hospital, Changchun, 130062, China
| | - Xuefei Wang
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Wenjing Luan
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Fangxue Ma
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Lihui Ni
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China
| | - Mingyuan Liu
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China
| | - Lu Yu
- Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Department of Infectious Diseases of First Hospital of Jilin University, Changchun, 130062, China.
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Nia AM, Khanipov K, Barnette BL, Ullrich RL, Golovko G, Emmett MR. Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma. BMC Genomics 2020; 21:453. [PMID: 32611366 PMCID: PMC7329445 DOI: 10.1186/s12864-020-06869-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/24/2020] [Indexed: 01/04/2023] Open
Abstract
Background One of the health risks posed to astronauts during deep space flights is exposure to high charge, high-energy (HZE) ions (Z > 13), which can lead to the induction of hepatocellular carcinoma (HCC). However, little is known on the molecular mechanisms of HZE irradiation-induced HCC. Results We performed comparative RNA-Seq transcriptomic analyses to assess the carcinogenic effects of 600 MeV/n 56Fe (0.2 Gy), 1 GeV/n 16O (0.2 Gy), and 350 MeV/n 28Si (0.2 Gy) ions in a mouse model for irradiation-induced HCC. C3H/HeNCrl mice were subjected to total body irradiation to simulate space environment HZE-irradiation, and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent carcinogenic response at the transcriptomic level. Our data demonstrated a clear difference in the biological effects of these HZE ions, particularly immunological, such as Acute Phase Response Signaling, B Cell Receptor Signaling, IL-8 Signaling, and ROS Production in Macrophages. Also seen in this study were novel unannotated transcripts that were significantly affected by HZE. To investigate the biological functions of these novel transcripts, we used a machine learning technique known as self-organizing maps (SOMs) to characterize the transcriptome expression profiles of 60 samples (45 HZE-irradiated, 15 non-irradiated control) from liver tissues. A handful of localized modules in the maps emerged as groups of co-regulated and co-expressed transcripts. The functional context of these modules was discovered using overrepresentation analysis. We found that these spots typically contained enriched populations of transcripts related to specific immunological molecular processes (e.g., Acute Phase Response Signaling, B Cell Receptor Signaling, IL-3 Signaling), and RNA Transcription/Expression. Conclusions A large number of transcripts were found differentially expressed post-HZE irradiation. These results provide valuable information for uncovering the differences in molecular mechanisms underlying HZE specific induced HCC carcinogenesis. Additionally, a handful of novel differentially expressed unannotated transcripts were discovered for each HZE ion. Taken together, these findings may provide a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation and may also have important implications for the discovery of potential countermeasures against and identification of biomarkers for HZE-induced HCC.
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Affiliation(s)
- Anna M Nia
- Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Kamil Khanipov
- Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Brooke L Barnette
- Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Robert L Ullrich
- The Radiation Effects Research Foundation (RERF), Hiroshima, Japan
| | - George Golovko
- Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Mark R Emmett
- Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA. .,Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA.
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50
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Kiffer F, Alexander T, Anderson J, Groves T, McElroy T, Wang J, Sridharan V, Bauer M, Boerma M, Allen A. Late Effects of 1H + 16O on Short-Term and Object Memory, Hippocampal Dendritic Morphology and Mutagenesis. Front Behav Neurosci 2020; 14:96. [PMID: 32670032 PMCID: PMC7332779 DOI: 10.3389/fnbeh.2020.00096] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 05/22/2020] [Indexed: 11/17/2022] Open
Abstract
The space extending beyond Earth’s magnetosphere is subject to a complex field of high-energy charged nuclei, which are capable of traversing spacecraft shielding and human tissues, inducing dense ionization events. The central nervous system is a major area of concern for astronauts who will be exposed to the deep-space radiation environment on a mission to Mars, as charged-particle radiation has been shown to elicit changes to the dendritic arbor within the hippocampus of rodents, and related cognitive-behavioral deficits. We exposed 6-month-old male mice to whole-body 1H (0.5 Gy; 150 MeV/n; 18–19 cGy/minute) and an hour later to 16O (0.1Gy; 600 MeV/n; 18–33 Gy/min) at NASA’s Space Radiation Laboratory as a galactic cosmic ray-relevant model. Animals were housed with bedding which provides cognitive enrichment. Mice were tested for cognitive behavior 9 months after exposure to elucidate late radiation effects. Radiation induced significant deficits in novel object recognition and short-term spatial memory (Y-maze). Additionally, we observed opposing morphological differences between the mature granular and pyramidal neurons throughout the hippocampus, with increased dendritic length in the dorsal dentate gyrus and reduced length and complexity in the CA1 subregion of the hippocampus. Dendritic spine analyses revealed a severe reduction in mushroom spine density throughout the hippocampus of irradiated animals. Finally, we detected no general effect of radiation on single-nucleotide polymorphisms in immediate early genes, and genes involved in inflammation but found a higher variant allele frequency in the antioxidants thioredoxin reductase 2 and 3 loci.
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Affiliation(s)
- Frederico Kiffer
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Tyler Alexander
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Julie Anderson
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Thomas Groves
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Taylor McElroy
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Jing Wang
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Vijayalakshmi Sridharan
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Michael Bauer
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Marjan Boerma
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Antiño Allen
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.,Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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