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Yu J, Ren L, Wu T, Hua L, Wang D, Wang Y, Xie Q, Deng J, Gong Y. Establishment and transcriptomic characteristics of radio-resistant meningioma cell lines. J Neurooncol 2025; 173:105-119. [PMID: 40019713 DOI: 10.1007/s11060-025-04966-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 02/05/2025] [Indexed: 03/01/2025]
Abstract
PURPOSE Radio-resistance poses a significant challenge in meningioma treatment. This study aimed to establish radio-resistant meningioma cell lines and uncover molecular mechanisms driving radio-resistance to identify potential biomarkers and therapeutic targets. METHODS Radio-resistant meningioma cell lines (IOMM-Lee-RR, CH157-RR) were developed using a progressive radiation dose (cumulative 90 Gy). Cell morphology, radiosensitivity, apoptosis, viability, migration, invasion, cell cycle, and DNA damage repair were analyzed via clonogenic assays, flow cytometry, and Western blotting. Transcriptome sequencing was performed to identify differentially expressed genes (DEGs), followed by KEGG and GO enrichment analyses. Protein-protein interaction (PPI) analysis was conducted to identify hub genes. TK1 expression was further validated in a cohort of 350 meningiomas and the GSE189672 dataset. RESULTS Radio-resistant meningioma cell lines exhibited enhanced survival, reduced apoptosis, increased cell viability, and superior migratory and invasive abilities compared to parental cells. Under radiation, these cells showed G0/G1 phase accumulation and reduced G2/M phase arrest, along with enhanced DNA repair capacity, as evidenced by lower γ-H2AX expression and fewer DNA damage foci. Transcriptome analysis revealed significant enrichment in metabolic pathways, DNA repair, and cell cycle regulation. Among 34 hub genes identified, TK1 emerged as a key gene, being highly expressed in recurrent and high-grade meningiomas and positively correlated with Ki67. Analysis of the GSE189672 dataset confirmed TK1 as a poor prognostic factor associated with tumor recurrence. CONCLUSION Radio-resistant meningioma cells exhibit enhanced DNA repair, migration, invasion, and altered cell cycle dynamics. TK1 was identified as a promising biomarker and therapeutic target for overcoming radio-resistance in meningiomas.
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Affiliation(s)
- Jinxiu Yu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China
- Institute of Neurosurgery, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China
| | - Leihao Ren
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China
- Institute of Neurosurgery, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China
| | - Tianqi Wu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China
- Institute of Neurosurgery, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China
| | - Lingyang Hua
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China
- Institute of Neurosurgery, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China
| | - Daijun Wang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China
- Institute of Neurosurgery, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China
| | - Yang Wang
- Department of Radiotherapy, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qing Xie
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China
- Institute of Neurosurgery, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China
| | - Jiaojiao Deng
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China.
- Institute of Neurosurgery, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China.
| | - Ye Gong
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China.
- Institute of Neurosurgery, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Fudan University, Shanghai, China.
- Department of Critical Care Medicine, Shanghai Medical College, Huashan Hospital, Fudan University, Shanghai, China.
- Department of Neurosurgery, Department of Critical Care Medicine, Shanghai Medical College, Huashan Hospital, Fudan University, No. 12 Middle Wulumuqi Road, Jingan District, Shanghai, 200040, China.
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Jeong J, Taasti VT, Jackson A, Gouw ZAR, Simone CB, Lambin P, Deasy JO. The fractionation dependence of tumor control in proton therapy for early-stage non-small cell lung cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.23.632803. [PMID: 39896536 PMCID: PMC11785185 DOI: 10.1101/2025.01.23.632803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Purpose The relative biological effectiveness (RBE) of tumor control for proton beam therapy (PBT) compared to photon radiotherapy (RT) is typically assumed to be independent of fractionation. To test this, we modeled published PBT outcome results for early-stage non-small cell lung cancer (NSCLC) treatments across a range of fractionation schedules. Materials and Methods All published and analyzable cohorts were included (399 patients, 413 treated lesions). Two models were used to fit the data: a previously published tumor simulation model that fits photon RT results of NSCLC across all fractionation regimes and the Fowler LQ model with a kick-off time term. The treatment effect of each cohort was referenced to the photon equivalent dose through mechanistic model simulations in a 2 Gy/weekday scenario, with radiobiological parameters determined to simultaneously best-fit all fractionation results. The tumor control RBE of each published treatment schedule, compared to the modeled photon RT effect of the same schedule, was then estimated. Results For cohorts whose treatments lasted less than three weeks (i.e., 12 fractions or less), the RBE of PBT was in the range of 1.08 to 1.11. However, for fractionated treatments stretching over four weeks or more (20-25 fractions), the relative effectiveness was much lower, with RBEs in the range of 0.82-0.89. This conclusion was unchanged using the simpler Fowler LQ + time model. Conclusions The proton RBE for hypo-fractionated schedules was 20-30% higher than for conventional schedules. The derived radiobiological parameters of PBT differ significantly from those of photon RT, indicating that PBT is influenced differentially by radiobiological mechanisms which require further investigation.
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Cosper PF, Paracha M, Jones KM, Hrycyniak L, Henderson L, Bryan A, Eyzaguirre D, McCunn E, Boulanger E, Wan J, Nickel KP, Horner V, Hu R, Harari PM, Kimple RJ, Weaver BA. Chromosomal instability increases radiation sensitivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.13.612942. [PMID: 39345631 PMCID: PMC11429890 DOI: 10.1101/2024.09.13.612942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Continuous chromosome missegregation over successive mitotic divisions, known as chromosomal instability (CIN), is common in cancer. Increasing CIN above a maximally tolerated threshold leads to cell death due to loss of essential chromosomes. Here, we show in two tissue contexts that otherwise isogenic cancer cells with higher levels of CIN are more sensitive to ionizing radiation, which itself induces CIN. CIN also sensitizes HPV-positive and HPV-negative head and neck cancer patient derived xenograft (PDX) tumors to radiation. Moreover, laryngeal cancers with higher CIN prior to treatment show improved response to radiation therapy. In addition, we reveal a novel mechanism of radiosensitization by docetaxel, a microtubule stabilizing drug commonly used in combination with radiation. Docetaxel causes cell death by inducing CIN due to abnormal multipolar spindles rather than causing mitotic arrest, as previously assumed. Docetaxel-induced CIN, rather than mitotic arrest, is responsible for the enhanced radiation sensitivity observed in vitro and in vivo, challenging the mechanistic dogma of the last 40 years. These results implicate CIN as a potential biomarker and inducer of radiation response, which could provide valuable cancer therapeutic opportunities. Statement of Significance Cancer cells and laryngeal tumors with higher chromosome missegregation rates are more sensitive to radiation therapy, supporting chromosomal instability as a promising biomarker of radiation response.
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Affiliation(s)
- Pippa F. Cosper
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Maha Paracha
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kathryn M. Jones
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Laura Hrycyniak
- Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin, Madison, WI 53705, USA
| | - Les Henderson
- Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, WI
| | - Ava Bryan
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Diego Eyzaguirre
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Emily McCunn
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Elizabeth Boulanger
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Jun Wan
- Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kwangok P. Nickel
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Vanessa Horner
- Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, WI
| | - Rong Hu
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Paul M. Harari
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Randall J. Kimple
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Beth A. Weaver
- University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53705, USA
- Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA
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Edelmann M, Fan S, De Oliveira T, Goldhardt T, Sartorius D, Midelashvili T, Conrads K, Paul NB, Beißbarth T, Fleischer JR, Blume ML, Bohnenberger H, Josipovic N, Papantonis A, Linnebacher M, Dröge LH, Ghadimi M, Rieken S, Conradi LC. Tumor Vessel Normalization via PFKFB3 Inhibition Alleviates Hypoxia and Increases Tumor Necrosis in Rectal Cancer upon Radiotherapy. CANCER RESEARCH COMMUNICATIONS 2024; 4:2008-2024. [PMID: 39007350 PMCID: PMC11310748 DOI: 10.1158/2767-9764.crc-24-0077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 05/22/2024] [Accepted: 07/11/2024] [Indexed: 07/16/2024]
Abstract
Treatment of patients with locally advanced rectal cancer (RC) is based on neoadjuvant chemoradiotherapy followed by surgery. In order to reduce the development of therapy resistance, it is necessary to further improve previous treatment approaches. Recent in vivo experimental studies suggested that the reduction of tumor hypoxia by tumor vessel normalization (TVN), through the inhibition of the glycolytic activator PFKFB3, could significantly improve tumor response to therapy. We have evaluated in vitro and in vivo the effects of the PFKFB3 inhibitor 2E-3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) on cell survival, clonogenicity, migration, invasion, and metabolism using colorectal cancer cells, patient-derived tumor organoid (PDO), and xenograft (PDX). 3PO treatment of colorectal cancer cells increased radiation-induced cell death and reduced cancer cell invasion. Moreover, gene set enrichment analysis shows that 3PO is able to alter the metabolic status of PDOs toward oxidative phosphorylation. Additionally, in vivo neoadjuvant treatment with 3PO induced TVN, alleviated tumor hypoxia, and increased tumor necrosis. Our results support PFKFB3 inhibition as a possible future neoadjuvant addition for patients with RC. SIGNIFICANCE Novel therapies to better treat colorectal cancer are necessary to improve patient outcomes. Therefore, in this study, we evaluated the combination of a metabolic inhibitor (3PO) and standard radiotherapy in different experimental settings. We have observed that the addition of 3PO increased radiation effects, ultimately improving tumor cell response to therapy.
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Affiliation(s)
- Marcus Edelmann
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Shuang Fan
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Tiago De Oliveira
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Tina Goldhardt
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Dorothée Sartorius
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Teona Midelashvili
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Karly Conrads
- Department for Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Germany.
| | - Niels B. Paul
- Department for Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Germany.
| | - Tim Beißbarth
- Department for Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Germany.
| | - Johannes R. Fleischer
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Moritz L. Blume
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Hanibal Bohnenberger
- Institute for Pathology, University Medical Center Göttingen, Göttingen, Germany.
| | - Natasa Josipovic
- Institute for Pathology, University Medical Center Göttingen, Göttingen, Germany.
| | - Argyris Papantonis
- Institute for Pathology, University Medical Center Göttingen, Göttingen, Germany.
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Department of General, Visceral, Vascular and Transplantation Surgery, University of Rostock, Rostock, Germany.
| | - Leif H. Dröge
- Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany.
| | - Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
| | - Stefan Rieken
- Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Göttingen, Germany.
| | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
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Matsuya Y, Sato T, Kusumoto T, Yachi Y, Seino R, Miwa M, Ishikawa M, Matsuyama S, Fukunaga H. Cell-cycle dependence on the biological effects of boron neutron capture therapy and its modification by polyvinyl alcohol. Sci Rep 2024; 14:16696. [PMID: 39030350 PMCID: PMC11271528 DOI: 10.1038/s41598-024-67041-6] [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: 04/15/2024] [Accepted: 07/08/2024] [Indexed: 07/21/2024] Open
Abstract
Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-L-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G2/M phase was higher than that in the G1/S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents.
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Affiliation(s)
- Yusuke Matsuya
- Nuclear Science and Engineering Center, Japan Atomic Energy Agency, Tokai, 319-1195, Japan.
- Faculty of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
| | - Tatsuhiko Sato
- Nuclear Science and Engineering Center, Japan Atomic Energy Agency, Tokai, 319-1195, Japan
| | - Tamon Kusumoto
- National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan
| | - Yoshie Yachi
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Ryosuke Seino
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Misako Miwa
- Department of Quantum Science and Energy Engineering, Graduate School of Engineering, Tohoku University, Sendai, 980-8579, Japan
| | - Masayori Ishikawa
- Faculty of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Shigeo Matsuyama
- Department of Quantum Science and Energy Engineering, Graduate School of Engineering, Tohoku University, Sendai, 980-8579, Japan
| | - Hisanori Fukunaga
- Faculty of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
- Center for Environmental and Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
- Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.
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Niu Z, Yang Z, Sun S, Zeng Z, Han Q, Wu L, Bai J, Li H, Xia H. Clinical analysis of the efficacy of radiation therapy for primary high-grade gliomas guided by biological rhythms. Transl Oncol 2024; 45:101973. [PMID: 38705052 PMCID: PMC11089398 DOI: 10.1016/j.tranon.2024.101973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/05/2024] [Accepted: 04/20/2024] [Indexed: 05/07/2024] Open
Abstract
OBJECTIVE High-grade glioma (HGG) patients frequently encounter treatment resistance and relapse, despite numerous interventions seeking enhanced survival outcomes yielding limited success. Consequently, this study, rooted in our prior research, aimed to ascertain whether leveraging circadian rhythm phase attributes could optimize radiotherapy results. METHODS In this retrospective analysis, we meticulously selected 121 HGG cases with synchronized rhythms through Cosinor analysis. Post-surgery, all subjects underwent standard radiotherapy alongside Temozolomide chemotherapy. Random allocation ensued, dividing patients into morning (N = 69) and afternoon (N = 52) radiotherapy cohorts, enabling a comparison of survival and toxicity disparities. RESULTS The afternoon radiotherapy group exhibited improved overall survival (OS) and progression-free survival (PFS) relative to the morning cohort. Notably, median OS extended to 25.6 months versus 18.5 months, with P = 0.014, with median PFS at 20.6 months versus 13.3 months, with P = 0.022, post-standardized radiotherapy. Additionally, lymphocyte expression levels in the afternoon radiation group 32.90(26.10, 39.10) significantly exceeded those in the morning group 31.30(26.50, 39.20), with P = 0.032. CONCLUSIONS This study underscores the markedly prolonged average survival within the afternoon radiotherapy group. Moreover, lymphocyte proportion demonstrated a notable elevation in the afternoon group. Timely and strategic adjustments of therapeutic interventions show the potential to improve therapeutic efficacy, while maintaining vigilant systemic immune surveillance. A comprehensive grasp of physiological rhythms governing both the human body and tumor microenvironment can refine treatment efficacy, concurrently curtailing immune-related damage-a crucial facet of precision medicine.
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Affiliation(s)
- Zhanfeng Niu
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China
| | - Zhihua Yang
- Department of Radiation Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China
| | - Shengyu Sun
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China
| | - Zhong Zeng
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China; Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China
| | - Qian Han
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China; Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China
| | - Liang Wu
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China
| | - Jinbo Bai
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China
| | - Hailiang Li
- Department of Radiation Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China
| | - Hechun Xia
- Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, PR China; Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, PR China.
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Yamashita K, Yasui H, Bo T, Fujimoto M, Inanami O. Mechanism of the Radioresistant Colorectal Cancer Cell Line SW480RR Established after Fractionated X Irradiation. Radiat Res 2024; 202:38-50. [PMID: 38779845 DOI: 10.1667/rade-23-00021.1] [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: 02/07/2023] [Accepted: 05/08/2024] [Indexed: 05/25/2024]
Abstract
Radioresistant cancer cells are risk factors for recurrence and are occasionally detected in recurrent tumors after radiotherapy. Intratumor heterogeneity is believed to be a potential cause of treatment resistance. Heterogeneity in DNA content has also been reported in human colorectal cancer; however, little is known about how such heterogeneity changes with radiotherapy or how it affects cancer radioresistance. In the present study, we established radioresistant clone SW480RR cells after fractionated X-ray irradiation of human colorectal cancer-derived SW480.hu cells, which are composed of two cell populations with different chromosome numbers, and examined how cellular radioresistance changed with fractionated radiotherapy. Compared with the parental cell population, which mostly comprised cells with higher ploidy, the radioresistant clones showed lower ploidy and less initial DNA damage. The lower ploidy cells in the parental cell population were identified as having radioresistance prior to irradiation; thus, SW480RR cells were considered intrinsically radioresistant cells selected from the parental population through fractionated irradiation. This study presents a practical example of the emergence of radioresistant cells from a cell population with ploidy heterogeneity after irradiation. The most likely mechanism is the selection of an intrinsically radioresistant population after fractionated X-ray irradiation, with a background in which lower ploidy cells exhibit lower initial DNA damage.
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Affiliation(s)
- Koya Yamashita
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Hironobu Yasui
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Tomoki Bo
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Masaki Fujimoto
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Osamu Inanami
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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Matsuya Y, Sato T, Yachi Y, Date H, Hamada N. The impact of dose rate on responses of human lens epithelial cells to ionizing irradiation. Sci Rep 2024; 14:12160. [PMID: 38802452 PMCID: PMC11130169 DOI: 10.1038/s41598-024-62679-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/20/2024] [Indexed: 05/29/2024] Open
Abstract
The knowledge on responses of human lens epithelial cells (HLECs) to ionizing radiation exposure is important to understand mechanisms of radiation cataracts that are of concern in the field of radiation protection and radiation therapy. However, biological effects in HLECs following protracted exposure have not yet fully been explored. Here, we investigated the temporal kinetics of γ-H2AX foci as a marker for DNA double-strand breaks (DSBs) and cell survival in HLECs after exposure to photon beams at various dose rates (i.e., 150 kVp X-rays at 1.82, 0.1, and 0.033 Gy/min, and 137Cs γ-rays at 0.00461 Gy/min (27.7 cGy/h) and 0.00081 Gy/min (4.9 cGy/h)), compared to those in human lung fibroblasts (WI-38). In parallel, we quantified the recovery for DSBs and cell survival using a biophysical model. The study revealed that HLECs have a lower DSB repair rate than WI-38 cells. There is no significant impact of dose rate on cell survival in both cell lines in the dose-rate range of 0.033-1.82 Gy/min. In contrast, the experimental residual γ-H2AX foci showed inverse dose rate effects (IDREs) compared to the model prediction, highlighting the importance of the IDREs in evaluating radiation effects on the ocular lens.
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Affiliation(s)
- Yusuke Matsuya
- Faculty of Health Sciences, Hokkaido University, Kita-12 Nishi-5, Kita-ku, Sapporo, 060-0812, Japan.
- Research Group for Radiation Transport Analysis, Nuclear Science and Engineering Center, Japan Atomic Energy Agency (JAEA), 2-4 Shirakata, Tokai, Ibaraki, 319-1195, Japan.
| | - Tatsuhiko Sato
- Research Group for Radiation Transport Analysis, Nuclear Science and Engineering Center, Japan Atomic Energy Agency (JAEA), 2-4 Shirakata, Tokai, Ibaraki, 319-1195, Japan
| | - Yoshie Yachi
- Graduate School of Health Sciences, Hokkaido University, Kita-12 Nishi-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
| | - Hiroyuki Date
- Faculty of Health Sciences, Hokkaido University, Kita-12 Nishi-5, Kita-ku, Sapporo, 060-0812, Japan
| | - Nobuyuki Hamada
- Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry (CRIEPI), Chiba, 270-1194, Japan.
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Nojima H, Kaida A, Matsuya Y, Uo M, Yoshimura RI, Arazi L, Miura M. DNA damage response in a 2D-culture model by diffusing alpha-emitters radiation therapy (Alpha-DaRT). Sci Rep 2024; 14:11468. [PMID: 38769339 PMCID: PMC11106084 DOI: 10.1038/s41598-024-62071-6] [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: 12/09/2023] [Accepted: 05/13/2024] [Indexed: 05/22/2024] Open
Abstract
Diffusing alpha-emitters radiation therapy (Alpha-DaRT) is a unique method, in which interstitial sources carrying 224Ra release a chain of short-lived daughter atoms from their surface. Although DNA damage response (DDR) is crucial to inducing cell death after irradiation, how the DDR occurs during Alpha-DaRT treatment has not yet been explored. In this study, we temporo-spatially characterized DDR such as kinetics of DNA double-strand breaks (DSBs) and cell cycle, in two-dimensional (2D) culture conditions qualitatively mimicking Alpha-DaRT treatments, by employing HeLa cells expressing the Fucci cell cycle-visualizing system. The distribution of the alpha-particle pits detected by a plastic nuclear track detector, CR-39, strongly correlated with γH2AX staining, a marker of DSBs, around the 224Ra source, but the area of G2 arrested cells was more widely spread 24 h from the start of the exposure. Thereafter, close time-lapse observation revealed varying cell cycle kinetics, depending on the distance from the source. A medium containing daughter nuclides prepared from 224Ra sources allowed us to estimate the radiation dose after 24 h of exposure, and determine surviving fractions. The present experimental model revealed for the first time temporo-spatial information of DDR occurring around the source in its early stages.
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Affiliation(s)
- Hitomi Nojima
- Department of Dental Radiology and Radiation Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan
| | - Atsushi Kaida
- Department of Dental Radiology and Radiation Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan
| | - Yusuke Matsuya
- Nuclear Science and Engineering Center, Japan Atomic Energy Agency, 2-4 Shirakata, Tokai, Ibaraki, 319-1195, Japan
- Faculty of Health Sciences, Hokkaido University, Kita-12 Nishi-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
| | - Motohiro Uo
- Department of Advanced Biomaterials, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan
| | - Ryo-Ichi Yoshimura
- Department of Radiation Therapeutics and Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan
| | - Lior Arazi
- Unit of Nuclear Engineering, Faculty of Engineering Sciences, Ben-Gurion University of the Negev, P.O.B. 653, 8410501, Be'er-Sheva, Israel
| | - Masahiko Miura
- Department of Dental Radiology and Radiation Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.
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10
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Buckley CE, O’Brien RM, Nugent TS, Donlon NE, O’Connell F, Reynolds JV, Hafeez A, O’Ríordáin DS, Hannon RA, Neary P, Kalbassi R, Mehigan BJ, McCormick PH, Dunne C, Kelly ME, Larkin JO, O’Sullivan J, Lynam-Lennon N. Metformin is a metabolic modulator and radiosensitiser in rectal cancer. Front Oncol 2023; 13:1216911. [PMID: 37601689 PMCID: PMC10435980 DOI: 10.3389/fonc.2023.1216911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer.
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Affiliation(s)
- Croí E. Buckley
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Rebecca M. O’Brien
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Timothy S. Nugent
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | - Noel E. Donlon
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Department of Surgery, Beacon Hospital, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Fiona O’Connell
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - John V. Reynolds
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Adnan Hafeez
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | | | | | - Paul Neary
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | - Reza Kalbassi
- Department of Surgery, Beacon Hospital, Dublin, Ireland
| | - Brian J. Mehigan
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Paul H. McCormick
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Cara Dunne
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Michael E. Kelly
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - John O. Larkin
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
- Gastrointestinal Medicine and Surgery (GEMS) Directorate, St. James’s Hospital, Dublin, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
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11
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Tallman MM, Zalenski AA, Stabl I, Schrock MS, Kollin L, de Jong E, De K, Grubb TM, Summers MK, Venere M. Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11. Cancers (Basel) 2023; 15:3173. [PMID: 37370783 DOI: 10.3390/cancers15123173] [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: 05/15/2023] [Revised: 05/31/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials.
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Affiliation(s)
- Miranda M Tallman
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA
| | - Abigail A Zalenski
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Neuroscience Graduate Program, The Ohio State University, Columbus, OH 43210, USA
| | - Ian Stabl
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Morgan S Schrock
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Luke Kollin
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Eliane de Jong
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Kuntal De
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Treg M Grubb
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Matthew K Summers
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Monica Venere
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
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12
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Beddok A, Porte B, Cottu P, Fourquet A, Kirova Y. [Biological, preclinical and clinical aspects of the association between radiation therapy and CDK4/6 inhibitors]. Cancer Radiother 2023; 27:240-248. [PMID: 37080859 DOI: 10.1016/j.canrad.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 10/06/2022] [Accepted: 11/30/2022] [Indexed: 04/22/2023]
Abstract
Several clinical studies have shown that CDK4/6 inhibitors (CDK4/6i) improve survival in patients with metastatic or locally advanced HR-positive, HER-2-negative breast cancer (BC). The aim of this review was to synthesize the biological, preclinical and clinical aspects of the treatment of BC with CDK4/6i, with a focus on the combination of CDK4/6i and radiotherapy. The DNA damage induced after exposure of cells to ionizing radiation activates control pathways that inhibit cell progression in the G1 and G2 phases and induce a transient delay in progression in the S phase. These checkpoints are in particular mediated by cyclin-dependent kinases (CDK) 4/6 activated by cyclin D1. Several preclinical studies have shown that CDK4/6i could be used as radiosensitizers in non-small cell lung cancer, medulloblastoma, brainstem glioma and breast cancer. CDK4/6 inhibition also protected against radiation-induced intestinal toxicities by inducing redistribution of quiescent intestinal progenitor cells, making them less radiosensitive. Clinical data on the combination of CDK inhibitors and radiotherapy for both locoregional and metastatic irradiation are based on retrospective data. Nevertheless, the most optimal therapeutic sequence would be radiotherapy followed by palbociclib. Pending prospective clinical trials, the concomitant combination of the two treatments should be done under close supervision.
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Affiliation(s)
- A Beddok
- Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO, 91898 Orsay, France; Institut Curie, PSL Research University, Radiation Oncology Department, Proton Therapy Centre, Centre Universitaire, 91898 Orsay, France.
| | - B Porte
- Service d'oncologie médicale, GHU hôpital européen Georges-Pompidou, Paris, France
| | - P Cottu
- Département d'oncologie médicale, Institut Curie, Paris, France
| | - A Fourquet
- Institut Curie, PSL Research University, Radiation Oncology Department, Paris, France
| | - Y Kirova
- Institut Curie, PSL Research University, Radiation Oncology Department, Paris, France
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13
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Buckley CE, Yin X, Meltzer S, Ree AH, Redalen KR, Brennan L, O'Sullivan J, Lynam-Lennon N. Energy Metabolism Is Altered in Radioresistant Rectal Cancer. Int J Mol Sci 2023; 24:ijms24087082. [PMID: 37108244 PMCID: PMC10138551 DOI: 10.3390/ijms24087082] [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: 01/10/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Resistance to neoadjuvant chemoradiation therapy is a significant clinical challenge in the management of rectal cancer. There is an unmet need to identify the underlying mechanisms of treatment resistance to enable the development of biomarkers predictive of response and novel treatment strategies to improve therapeutic response. In this study, an in vitro model of inherently radioresistant rectal cancer was identified and characterized to identify mechanisms underlying radioresistance in rectal cancer. Transcriptomic and functional analysis demonstrated significant alterations in multiple molecular pathways, including the cell cycle, DNA repair efficiency and upregulation of oxidative phosphorylation-related genes in radioresistant SW837 rectal cancer cells. Real-time metabolic profiling demonstrated decreased reliance on glycolysis and enhanced mitochondrial spare respiratory capacity in radioresistant SW837 cells when compared to radiosensitive HCT116 cells. Metabolomic profiling of pre-treatment serum samples from rectal cancer patients (n = 52) identified 16 metabolites significantly associated with subsequent pathological response to neoadjuvant chemoradiation therapy. Thirteen of these metabolites were also significantly associated with overall survival. This study demonstrates, for the first time, a role for metabolic reprograming in the radioresistance of rectal cancer in vitro and highlights a potential role for altered metabolites as novel circulating predictive markers of treatment response in rectal cancer patients.
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Affiliation(s)
- Croí E Buckley
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Xiaofei Yin
- UCD School of Agriculture and Food Science, UCD Institute of Food and Health, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Sebastian Meltzer
- Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway
| | - Anne Hansen Ree
- Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway
| | - Kathrine Røe Redalen
- Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Lorraine Brennan
- UCD School of Agriculture and Food Science, UCD Institute of Food and Health, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Jacintha O'Sullivan
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
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14
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Leblanc A, Thomas TV, Bouganim N. Chemoradiation for Locoregionally Advanced Laryngeal Cancer. Otolaryngol Clin North Am 2023; 56:285-293. [PMID: 37030941 DOI: 10.1016/j.otc.2022.12.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2023]
Abstract
Laryngeal preservation with combined modality therapy involving radiotherapy and chemotherapy is usually the treatment of choice for patients with good performance status and with locoregionally advanced laryngeal cancer with a functional larynx. Surgical management with total laryngectomy with neck dissection, followed by adjuvant radiation or chemoradiation, is recommended for patients not eligible for laryngeal preservation. This article provides an overview of the current therapeutic approaches used to treat locoregionally advanced laryngeal cancer and outlines other currently investigated therapies.
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Affiliation(s)
- Andréanne Leblanc
- Medical Oncology, Royal Victoria Hospital/Cedars Cancer Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3J1, Canada.
| | - Toms Vengaloor Thomas
- Dept of Radiation Oncology, University of Mississippi Medical Center, 2500 North State street, Jackson, MS, 39216, USA
| | - Nathaniel Bouganim
- Medical Oncology, Royal Victoria Hospital/Cedars Cancer Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3J1, Canada
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15
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Kuznetsov M, Kolobov A. Optimization of antitumor radiotherapy fractionation via mathematical modeling with account of 4 R's of radiobiology. J Theor Biol 2023; 558:111371. [PMID: 36462667 DOI: 10.1016/j.jtbi.2022.111371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/26/2022] [Accepted: 11/23/2022] [Indexed: 12/05/2022]
Abstract
A spatially-distributed continuous mathematical model of solid tumor growth and treatment by fractionated radiotherapy is presented. The model explicitly accounts for the factors, widely referred to as 4 R's of radiobiology, which influence the efficacy of radiotherapy fractionation protocols: tumor cell repopulation, their redistribution in cell cycle, reoxygenation and repair of sublethal damage of both tumor and normal tissues. With the use of special algorithm the fractionation protocols that provide increased tumor control probability, compared to standard clinical protocol, are found for various physiologically-based values of model parameters under the constraints of fixed overall normal tissue damage and maximum admissible fractional dose. In particular, it is shown that significant gain in treatment efficacy can be achieved for tumors of low malignancy by the use of protracted hyperfractionated protocols. The optimized non-uniform protocols are characterized by gradual escalation of fractional doses in their last parts, which start after the levels of oxygen and nutrients significantly elevate throughout the tumor and accelerated tumor proliferation manifests itself, which is a well-known experimental phenomenon.
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Affiliation(s)
- Maxim Kuznetsov
- P.N. Lebedev Physical Institute of the Russian Academy of Sciences, 53 Leninskiy Prospekt, Moscow 119991, Russia; Peoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
| | - Andrey Kolobov
- P.N. Lebedev Physical Institute of the Russian Academy of Sciences, 53 Leninskiy Prospekt, Moscow 119991, Russia
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16
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Du S, Liu Y, Yuan Y, Wang Y, Chen Y, Wang S, Chi Y. Advances in the study of HSP70 inhibitors to enhance the sensitivity of tumor cells to radiotherapy. Front Cell Dev Biol 2022; 10:942828. [PMID: 36036010 PMCID: PMC9399644 DOI: 10.3389/fcell.2022.942828] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
The 70 kDa heat shock protein (HSP70) is one of the most conserved proteins and a ubiquitous molecular chaperone that plays a role in the folding, remodeling, and degradation of various proteins to maintain proteostasis. It has been shown that HSP70 is abundantly expressed in cancer and enhances tumor resistance to radiotherapy by inhibiting multiple apoptotic pathways, such as interfering with the cellular senescence program, promoting angiogenesis, and supporting metastasis. Thus, HSP70 provides an effective target for enhancing the effects of radiation therapy in the clinical management of cancer patients. Inhibition of HSP70 enhances the radiation-induced tumor-killing effect and thus improves the efficacy of radiotherapy. This article reviews the sensitivity of Hsp70 and its related inhibitors to radiotherapy of tumor cells.
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Affiliation(s)
- Sihan Du
- School of Medical Imaging, Weifang Medical University, Weifang, Shandong, China
| | - Ying Liu
- School of Medical Imaging, Weifang Medical University, Weifang, Shandong, China
| | - Yuan Yuan
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yuran Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Yanfang Chen
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
| | - Shuai Wang
- Department of Radiotherapy, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
- *Correspondence: Shuai Wang, ; Yuhua Chi,
| | - Yuhua Chi
- Department of General Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China
- *Correspondence: Shuai Wang, ; Yuhua Chi,
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17
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Wu N, Zhang X, Zhu M, Fang C, Liu X, Wang Y, Li H, Liu S, Ting H, Qin C, Liao Q, Cai J, Wang J. ZNF582 promoter methylation predicts cervical cancer radiosensitivity and ZNF582 protein overexpression reduces radiosensitivity by cell cycle arrest in S phase. Epigenetics 2022; 17:1786-1799. [PMID: 35642528 DOI: 10.1080/15592294.2022.2080995] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
This study aimed to investigate the relationship between ZNF582 promoter methylation (ZNF582m) level and radiosensitivity of cervical cancer and its biological basis. This was a prospective multicenter clinical study, comprised of two independent cohorts of locally advanced cervical cancer patients. Exfoliated cervical cells were collected at 0, 24, 30, 36, 48, and 64 Gy to test ZNF582m levels. Radiotherapy response evaluated according to RECIST Version. RT-PCR, WT were used to detect the mRNA and protein expression levels; MTT, flow cytometry were used to detect the cell viability and cell cycle, respectively. While clone formation and subcutaneous tumorigenesis in nude mice were used to detect the growth of HeLa cells with/without ZNF582 overexpression. In the first cohort, 22 cases achieved complete remission (CR) or partial response (PR), and the other 28 cases exhibited stable disease (SD). Radiotherapy reduced ZNF582m levels among all patients. Initial lever of ZNF582m was significantly higher in the Responder (CR + PR) group than in SD group. Also, patients with higher initial lever ZNF582m were more sensitive toward radiotherapy than ZNF582m-low patients. The second cohort confirmed above results. The amplitude of ZNF582m levels were related to radiotherapeutic response; some patients of ZNF582m-low showed a transient increase in ZNF582m, and present greater radiosensitivity than other ZNF582m-low patients. In vitro, ZNF582 protein overexpression promoted cell cycle arrest in S phase. These results suggested that higher ZNF582m levels predicted greater radiosensitivity in clinical cervical cancer cases. Overexpressed ZNF582 conferred radioresistance by cell cycle arrest in vitro.
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Affiliation(s)
- Nayiyuan Wu
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xiaoyun Zhang
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,The second people's hospital of Yueyang City, Hunan, China
| | - Miaochen Zhu
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.,Graduate Collaborative Training Base of Hunan Cancer Hospital, University of South China, Hengyang, Hunan, China
| | - Chao Fang
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | | | - Ying Wang
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - He Li
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Siye Liu
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Hong Ting
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Chongzhen Qin
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qianjin Liao
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - JingTing Cai
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Jing Wang
- Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
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18
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The use of radiosensitizing agents in the therapy of glioblastoma multiforme-a comprehensive review. Strahlenther Onkol 2022; 198:507-526. [PMID: 35503461 PMCID: PMC9165247 DOI: 10.1007/s00066-022-01942-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/30/2022] [Indexed: 10/31/2022]
Abstract
BACKGROUND Glioblastoma is the most common malignant brain tumor in human adults. Despite several improvements in resective as well as adjuvant therapy over the last decades, its overall prognosis remains poor. As a means of improving patient outcome, the possibility of enhancing radiation response by using radiosensitizing agents has been tested in an array of studies. METHODS A comprehensive review of clinical trials involving radiation therapy in combination with radiosensitizing agents on patients diagnosed with glioblastoma was performed in the National Center for Biotechnology Information's PubMed database. RESULTS A total of 96 papers addressing this matter were published between 1976 and 2021, of which 63 matched the subject of this paper. All papers were reviewed, and their findings discussed in the context of their underlining mechanisms of radiosensitization. CONCLUSION In the history of glioblastoma treatment, several approaches of optimizing radiation-effectiveness using radiosensitizers have been made. Even though several different strategies and agents have been explored, clear evidence of improved patient outcome is still missing. Tissue-selectiveness and penetration of the blood-brain barrier seem to be major roadblocks; nevertheless, modern strategies try to circumvent these obstacles, using novel sensitizers based on preclinical data or alternative ways of delivery.
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19
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Guo XX, Guo ZH, Lu JS, Xie WS, Zhong QZ, Sun XD, Wang XM, Wang JY, Liu M, Zhao LY. All-purpose nanostrategy based on dose deposition enhancement, cell cycle arrest, DNA damage, and ROS production as prostate cancer radiosensitizer for potential clinical translation. NANOSCALE 2021; 13:14525-14537. [PMID: 34473816 DOI: 10.1039/d1nr03869a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Radiotherapy (RT) is one of the main treatments for men with prostate cancer (PCa). To date, numerous sophisticated nano-formulations as radiosensitizers have been synthesized with inspiring therapeutic effects both in vitro and in vivo; however, almost all the attention has been paid on the enhanced dose deposition effect by secondary electrons of nanomaterials with high atomic numbers (Z); despite this, cell-cycle arrest, DNA damage, and also reactive oxygen species (ROS) production are critical working mechanisms that account for radiosensitization. Herein, an 'all-purpose' nanostrategy based on dose deposition enhancement, cell cycle arrest, and ROS production as prostate cancer radiosensitizer for potential clinical translation was proposed. The rather simple structure of docetaxel-loaded Au nanoparticles (NPs) with prostate specific membrane antigen (PSMA) ligand conjugation have been successfully synthesized. Enhanced cellular uptake achieved via the selective internalization of the NPs by PCa cells with positive PSMA expression could guarantee enhanced dose deposition. Moreover, the as-synthesized nanosystem could effectively arrest the cell cycle at G2/M phases, which would reduce the ability of DNA damage repair for more irradiation sensitive of the PCa cells. Moreover, the G2/M phase arrest would further promote cascade retention and the enrichment of NPs within the cells. Furthermore, ROS generation and double strand breaks greatly promoted by NPs under irradiation (IR) could also provide an underlying basis for effective radiosensitizers. In vitro and in vivo investigations confirmed the as-synthesized NPs as an effective nano-radiosensitizer with ideal safety. More importantly, all moieties within the present nanosystem have been approved by FDA for the purpose of PCa treatment, thus making it highly attractive for clinical translation.
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Affiliation(s)
- Xiao-Xiao Guo
- Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
- Graduate School of Peking Union Medical College, Beijing, 100730, China
| | - Zhen-Hu Guo
- Key Laboratory of Advanced Materials, Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China
| | - Jing-Song Lu
- Key Laboratory of Advanced Materials, Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China
| | - Wen-Sheng Xie
- Key Laboratory of Advanced Materials, Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China
| | - Qiu-Zi Zhong
- Department of Radiotherapy, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Science, Beijing, 100730, China
| | - Xiao-Dan Sun
- Key Laboratory of Advanced Materials, Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China
| | - Xiu-Mei Wang
- Key Laboratory of Advanced Materials, Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China
| | - Jian-Ye Wang
- Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Ming Liu
- Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Ling-Yun Zhao
- Key Laboratory of Advanced Materials, Ministry of Education of China, School of Materials Science and Engineering, Tsinghua University, Beijing, 100084, China
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20
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Apilan AG, Mothersill C. Targeted and Non-Targeted Mechanisms for Killing Hypoxic Tumour Cells-Are There New Avenues for Treatment? Int J Mol Sci 2021; 22:8651. [PMID: 34445354 PMCID: PMC8395506 DOI: 10.3390/ijms22168651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/07/2021] [Accepted: 08/09/2021] [Indexed: 11/25/2022] Open
Abstract
PURPOSE A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new "target". Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. CONCLUSIONS This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled "oxygenate, target, use, and digest". In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.
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21
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Nardone V, Barbarino M, Angrisani A, Correale P, Pastina P, Cappabianca S, Reginelli A, Mutti L, Miracco C, Giannicola R, Giordano A, Pirtoli L. CDK4, CDK6/cyclin-D1 Complex Inhibition and Radiotherapy for Cancer Control: A Role for Autophagy. Int J Mol Sci 2021; 22:8391. [PMID: 34445095 PMCID: PMC8395054 DOI: 10.3390/ijms22168391] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/01/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
The expanding clinical application of CDK4- and CDK6-inhibiting drugs in the managements of breast cancer has raised a great interest in testing these drugs in other neoplasms. The potential of combining these drugs with other therapeutic approaches seems to be an interesting work-ground to explore. Even though a potential integration of CDK4 and CDK6 inhibitors with radiotherapy (RT) has been hypothesized, this kind of approach has not been sufficiently pursued, neither in preclinical nor in clinical studies. Similarly, the most recent discoveries focusing on autophagy, as a possible target pathway able to enhance the antitumor efficacy of CDK4 and CDK6 inhibitors is promising but needs more investigations. The aim of this review is to discuss the recent literature on the field in order to infer a rational combination strategy including cyclin-D1/CDK4-CDK6 inhibitors, RT, and/or other anticancer agents targeting G1-S phase cell cycle transition.
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Affiliation(s)
- Valerio Nardone
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (A.A.); (S.C.); (A.R.)
| | - Marcella Barbarino
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (M.B.); (A.G.)
| | - Antonio Angrisani
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (A.A.); (S.C.); (A.R.)
| | - Pierpaolo Correale
- Medical Oncology Unit, Grand Metropolitan Hospital “Bianchi-Melacrino-Morelli”, 89124 Reggio Calabria, Italy; (P.C.); (R.G.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19104, USA; (L.M.); (L.P.)
| | - Pierpaolo Pastina
- Section of Radiation Oncology, Medical School, University of Siena, 53100 Siena, Italy;
| | - Salvatore Cappabianca
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (A.A.); (S.C.); (A.R.)
| | - Alfonso Reginelli
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy; (A.A.); (S.C.); (A.R.)
| | - Luciano Mutti
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19104, USA; (L.M.); (L.P.)
| | - Clelia Miracco
- Pathological Anatomy Unit, Department of Medical, Surgical and Neurological Science, University of Siena, 53100 Siena, Italy;
| | - Rocco Giannicola
- Medical Oncology Unit, Grand Metropolitan Hospital “Bianchi-Melacrino-Morelli”, 89124 Reggio Calabria, Italy; (P.C.); (R.G.)
| | - Antonio Giordano
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (M.B.); (A.G.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19104, USA; (L.M.); (L.P.)
| | - Luigi Pirtoli
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19104, USA; (L.M.); (L.P.)
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22
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Dang TT, Morales JC. Loss of CENP-I Impairs Homologous Recombination and Sensitizes Cells to PARP1 Inhibition. Cancers (Basel) 2021; 13:3202. [PMID: 34206916 PMCID: PMC8267748 DOI: 10.3390/cancers13133202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 11/16/2022] Open
Abstract
Centromere Protein I (CENP-I) is a member of the CENP-H/I/K complex. CENP-H/I/K is a major component of the inner kinetochore and aids in ensuring proper chromosomal segregation during mitosis. In addition to this chromosomal segregation function, CENP-I also plays a role in DNA double-strand break (DSB) repair. Loss of CENP-I leads to increased endogenous 53BP1 foci and R-loop formation, while reducing cellular survival after ionizing radiation and Niraparib, a PARP1 small molecule inhibitor, exposures. Cells lacking CENP-I display delayed 53BP1 foci regression, an indication that DSB repair is impaired. Additionally, loss of CENP-I impairs the homologous recombination DSB repair pathway, while having no effect on the non-homologous end-joining pathway. Interestingly, we find that RNaseH1 expression restores HR capacity in CENP-I deficient cells. Importantly, CENP-I expression is elevated in glioma tissue as compared to normal brain tissue. This elevated expression also correlates with poor overall patient survival. These data highlight the multi-functional role CENP-I plays in maintaining genetic, as well as chromosomal, stability and tumor survival.
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Affiliation(s)
| | - Julio C. Morales
- Stephenson Cancer Center, Department of Neurosurgery, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA;
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23
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Manoharan D, Chang LC, Wang LC, Shan YS, Lin FC, Wu LC, Sheu HS, Su WP, Yeh CS. Synchronization of Nanoparticle Sensitization and Radiosensitizing Chemotherapy through Cell Cycle Arrest Achieving Ultralow X-ray Dose Delivery to Pancreatic Tumors. ACS NANO 2021; 15:9084-9100. [PMID: 33974409 DOI: 10.1021/acsnano.1c02283] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Pancreatic cancer is among the leading causes of cancer-related death and remains a formidable therapeutic challenge. To date, surgical resection and chemotherapy have been the standards of care. Methotrexate (MTX), which is recognized as a refractory drug for pancreatic cells, was conjugated to the surface of LiYF4:Ce3+ nanoparticles (NP-MTX) through a photocleavable linker molecule. When LiYF4:Ce3+ NPs are stimulated by X-rays, they emit light, which induces the photocleavage of the photolabile linker molecule to release MTX. MTX can target pancreatic tumors, which overexpress folic acid (FA) receptors and are internalized into the cell through receptor-mediated endocytosis. The synergistic effect of the NP-MTX treatment initiated by X-ray irradiation occurs due to the combination of nanoparticle sensitization and the radiosensitizing chemotherapy of the photocleaved MTX molecule. This dual sensitization effect mediated by NP-MTX enabled 40% dose enhancement, which corresponded with an increase in the generation of cytotoxic cellular reactive oxygen species (ROS) and enhanced S phase arrest within the cell cycle. The delivery of an ultralow radiation dose of 0.1 Gy resulted in the photocleavage of MTX from NP-MTX, and this strategy demonstrated in vivo efficacy against AsPC-1 and PANC-1 xenografted pancreatic tumors.
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Affiliation(s)
- Divinah Manoharan
- Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
| | - Li-Chan Chang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Liu-Chun Wang
- Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Forn-Chia Lin
- Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Lai-Chin Wu
- National Synchrotron Radiation Research Center, Hsinchu 300, Taiwan
| | - Hwo-Shuenn Sheu
- National Synchrotron Radiation Research Center, Hsinchu 300, Taiwan
| | - Wen-Pin Su
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Departments of Oncology and Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Chen-Sheng Yeh
- Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan 704, Taiwan
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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24
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Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence. Cells 2021; 10:cells10030610. [PMID: 33801903 PMCID: PMC7998378 DOI: 10.3390/cells10030610] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 12/19/2022] Open
Abstract
Double strand breaks (DSBs) are highly toxic to a cell, a property that is exploited in radiation therapy. A critical component for the damage induction is cellular oxygen, making hypoxic tumor areas refractory to the efficacy of radiation treatment. During a fractionated radiation regimen, these hypoxic areas can be re-oxygenated. Nonetheless, hypoxia still constitutes a negative prognostic factor for the patient’s outcome. We hypothesized that this might be attributed to specific hypoxia-induced cellular traits that are maintained upon reoxygenation. Here, we show that reoxygenation of hypoxic non-transformed RPE-1 cells fully restored induction of DSBs but the cells remain radioresistant as a consequence of hypoxia-induced quiescence. With the use of the cell cycle indicators (FUCCI), cell cycle-specific radiation sensitivity, the cell cycle phase duration with live cell imaging, and single cell tracing were assessed. We observed that RPE-1 cells experience a longer G1 phase under hypoxia and retain a large fraction of cells that are non-cycling. Expression of HPV oncoprotein E7 prevents hypoxia-induced quiescence and abolishes the radioprotective effect. In line with this, HPV-negative cancer cell lines retain radioresistance, while HPV-positive cancer cell lines are radiosensitized upon reoxygenation. Quiescence induction in hypoxia and its HPV-driven prevention was observed in 3D multicellular spheroids. Collectively, we identify a new hypoxia-dependent radioprotective phenotype due to hypoxia-induced quiescence that accounts for a global decrease in radiosensitivity that can be retained upon reoxygenation and is absent in cells expressing oncoprotein E7.
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25
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Ma JC, Zhong XR, Luo T, Xiang ZZ, Li JY, Luo C, Yan X, He P, Tian TL, Liu F, Liu L, Zheng H. The Effect of Postmastectomy Radiotherapy on Breast Cancer Patients After Neoadjuvant Chemotherapy by Molecular Subtype. Ann Surg Oncol 2021; 28:5084-5095. [PMID: 33580420 DOI: 10.1245/s10434-020-09523-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 12/08/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND The effect of postmastectomy radiotherapy (PMRT) on patient outcomes after neoadjuvant chemotherapy (NAC) remains controversial. We aimed to establish a model to identify the subsets benefiting from PMRT and to examine the effect of PMRT according to molecular subtype. PATIENTS AND METHODS We retrospectively analyzed 1118 cT1-4cN0-3M0 breast cancer patients treated with NAC and mastectomy. A nomogram predicting locoregional recurrence (LRR) was established based on 418 unirradiated patients, and X-tile analysis was performed to divide the patients into two risk groups. The effect of PMRT on LRR, distant recurrence (DR), and breast cancer mortality (BCM) was estimated for patients with different molecular subtypes in two risk groups. RESULTS A nomogram predicting LRR was developed using six factors: histologic classification, lymphovascular invasion, ypT stage, ypN stage, estrogen receptor status, and Ki-67 expression. Our study found that PMRT correlated with lower 5-year LRR, DR, and BCM rates for the high-risk group; however, no significant improvement in these endpoints was observed in the low-risk group. Among patients with high risk, subgroup analysis showed that LRR control was improved after PMRT for the human epidermal growth factor receptor 2 (HER2)-negative/hormone receptor (HR)-positive (HER2-/HR+), HER2-positive (HER2+)/HR+, and HER2-/HR-negative (HR-) subtypes, with hazard ratios of 0.113 (95% confidence [CI] 0.034-0.379; p < 0.001), 0.159 (95% CI 0.038-0.671; p = 0.017), and 0.243 (95% CI 0.088-0.676; p = 0.007), respectively, but not for the HER2+/HR- subtype (p = 0.468). CONCLUSIONS We built a nomogram showing favorable risk quantification and patient stratification. Patients in the high-risk group benefited from PMRT, but patients in the low-risk group did not. PMRT may show different benefits for each molecular subtype.
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Affiliation(s)
- Jia-Chun Ma
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Rong Zhong
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Luo
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhong-Zheng Xiang
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jia-Yuan Li
- Department of Epidemiology and Biostatistics, West China School of Public Health, Sichuan University, Chengdu, China
| | - Chuanxu Luo
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Yan
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ping He
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ting-Lun Tian
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Fang Liu
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Liu
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Zheng
- Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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26
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Koch RA, Harmel C, Alber M, Bahn E. A framework for automated time-resolved analysis of cell colony growth after irradiation. Phys Med Biol 2021; 66:035017. [PMID: 33264763 DOI: 10.1088/1361-6560/abd00d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Understanding dose-dependent survival of irradiated cells is a pivotal goal in radiotherapy and radiobiology. To this end, the clonogenic assay is the standard in vitro method, classifying colonies into either clonogenic or non-clonogenic based on a size threshold at a fixed time. Here we developed a methodological framework for the automated analysis of time course live-cell image data to examine in detail the growth dynamics of large numbers of colonies that occur during such an experiment. We developed a segmentation procedure that exploits the characteristic composition of phase-contrast images to identify individual colonies. Colony tracking allowed us to characterize colony growth dynamics as a function of dose by extracting essential information: (a) colony size distributions across time; (b) fractions of differential growth behavior; and (c) distributions of colony growth rates across all tested doses. We analyzed three data sets from two cell lines (H3122 and RENCA) and made consistent observations in line with already published results: (i) colony growth rates are normally distributed with a large variance; (ii) with increasing dose, the fraction of exponentially growing colonies decreases, whereas the fraction of delayed abortive colonies increases; as a novel finding, we observed that (iii) mean exponential growth rates decrease linearly with increasing dose across the tested range (0-10 Gy). The presented method is a powerful tool to examine live colony growth on a large scale and will help to deepen our understanding of the dynamic, stochastic processes underlying the radiation response in vitro.
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Affiliation(s)
- Robin A Koch
- Department of Radiation Oncology and Radiation Therapy, University Hospital Heidelberg, Germany
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27
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Sosa-Marrero C, de Crevoisier R, Hernandez A, Fontaine P, Rioux-Leclercq N, Mathieu R, Fautrel A, Paris F, Acosta O. Towards a Reduced In Silico Model Predicting Biochemical Recurrence After Radiotherapy in Prostate Cancer. IEEE Trans Biomed Eng 2021; 68:2718-2729. [PMID: 33460366 DOI: 10.1109/tbme.2021.3052345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE Purposes of this work were i) to develop an in silico model of tumor response to radiotherapy, ii) to perform an exhaustive sensitivity analysis in order to iii) propose a simplified version and iv) to predict biochemical recurrence with both the comprehensive and the reduced model. METHODS A multiscale computational model of tumor response to radiotherapy was developed. It integrated the following radiobiological mechanisms: oxygenation, including hypoxic death; division of tumor cells; VEGF diffusion driving angiogenesis; division of healthy cells and oxygen-dependent response to irradiation, considering, cycle arrest and mitotic catastrophe. A thorough sensitivity analysis using the Morris screening method was performed on 21 prostate computational tissues. Tumor control probability (TCP) curves of the comprehensive model and 15 reduced versions were compared. Logistic regression was performed to predict biochemical recurrence after radiotherapy on 76 localized prostate cancer patients using an output of the comprehensive and the reduced models. RESULTS No significant difference was found between the TCP curves of the comprehensive and a simplified version which only considered oxygenation, division of tumor cells and their response to irradiation. Biochemical recurrence predictions using the comprehensive and the reduced models improved those made from pre-treatment imaging parameters (AUC = 0.81 ± 0.02 and 0.82 ± 0.02 vs. 0.75 ± 0.03, respectively). CONCLUSION A reduced model of tumor response to radiotherapy able to predict biochemical recurrence in prostate cancer was obtained. SIGNIFICANCE This reduced model may be used in the future to optimize personalized fractionation schedules.
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28
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Brahme A. A DNA Repair-Based Model of Cell Survival with Important Clinical Consequences. Radiat Res 2020; 194:202-235. [PMID: 32942300 DOI: 10.1667/rade-20-00052.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 05/11/2020] [Indexed: 11/03/2022]
Abstract
This work provides a description of a new interaction, cross-section-based model for radiation-induced cellular inactivation, sublethal damage, DNA repair and cell survival, with the ability to more accurately elucidate different radiation-response phenomena. The principal goal of this work is to describe the damage-induction cross sections, as well as repair and survival, as Poisson processes with two main types of damage: mild damage that can be rapidly handled by the most basic repair processes; and more complex damage requiring longer repair times and the high-fidelity homologous recombination (HR) repair process to ensure accuracy and safety in the survival. This work is unique in its use of Poisson statistics to quantify the main repairable cell compartments that are exposed to simple and more complex sublethal hits, the cross section of which determines what is homologically and non-homologically repairable. The new method is applied to central radiation damage and survival data, such as in vitro cellular repair and survival with key DNA repair genes knocked out, low-dose hypersensitivity (LDHS), change in survival over the cell cycle, and variation with linear energy transfer (LET) for densely ionizing ions, all results supporting our basic assumptions. Among the results, it was shown that less than 1% of the simple DSBs are lethal at approximately 2 Gy and below for sparsely ionizing radiations, but their δ-electron track ends of between 1.5 and 0.5 keV can deliver 0.5 MGy to a few hundred nm3 volumes, mainly due to multiple scatter detours and multiple secondary electrons. They can cause dual double-strand breaks (DSBs) on the periphery of nucleosomes that are the most common multiply damaged sites, with an average of 1-2 δ-electron track ends per cell nucleus at 2 Gy. LDHS is most likely due to the normal lack of fast, efficient repair of sublethal damage below approximately 0.5 Gy, and requires largely intact key DNA repair genes to achieve significant repair recovery at higher doses. The new repair model describes this phenomenon quite accurately. Cells with key non-homologous end joining (NHEJ) genes knocked-out, lose LDHS but provoke HR repair, and cells with HR genes knocked out may lose some LDHS, but provoke NHEJ repair. The DNA duplication during the S phase results in a direct doubling as well of the total and sublethal hit cross sections. For the lowest LET carbon ions, NHEJ is reduced to where it is almost eliminated at maximum relative biological effectiveness (RBE), while HR is induced more than by X rays, due to complex damage and misrepair of DSBs produced by numerous δ electrons. The use of a lower LET such as electrons or photons during the final week of radiation treatment may potentially maximize complication-free cure. Optimally-designed weekly fractionation schedules are proposed to maximize the DNA repair potential in normal tissues. Additionally, the optimal therapeutic ion species, LET, apoptosis and permanent growth arrest/senescence window is identified with helium, lithium and boron ions and LETs at approximately 15-55 eV/nm, to maximize these quantities in the tumor and minimize them in the normal tissues, resulting in a very high probability of complication-free cure.
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Affiliation(s)
- Anders Brahme
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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29
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Fluctuation in radioresponse of HeLa cells during the cell cycle evaluated based on micronucleus frequency. Sci Rep 2020; 10:20873. [PMID: 33257719 PMCID: PMC7705701 DOI: 10.1038/s41598-020-77969-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 11/17/2020] [Indexed: 02/08/2023] Open
Abstract
In this study, we examined the fluctuation in radioresponse of HeLa cells during the cell cycle. For this purpose, we used HeLa cells expressing two types of fluorescent ubiquitination-based cell cycle indicators (Fucci), HeLa-Fucci (CA)2 and HeLa-Fucci (SA), and combined this approach with the micronucleus (MN) assay to assess radioresponse. The Fucci system distinguishes cell cycle phases based on the colour of fluorescence and cell morphology under live conditions. Time-lapse imaging allowed us to further identify sub-positions within the G1 and S phases at the time of irradiation by two independent means, and to quantitate the number of MNs by following each cell through M phase until the next G1 phase. Notably, we found that radioresponse was low in late G1 phase, but rapidly increased in early S phase. It then decreased until late S phase and increased in G2 phase. For the first time, we demonstrated the unique fluctuation of radioresponse by the MN assay during the cell cycle in HeLa cells. We discuss the difference between previous clonogenic experiments using M phase-synchronised cell populations and ours, as well as the clinical implications of the present findings.
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Sundaram A, Peng L, Chai L, Xie Z, Ponraj JS, Wang X, Wang G, Zhang B, Nie G, Xie N, Rajesh Kumar M, Zhang H. Advanced nanomaterials for hypoxia tumor therapy: challenges and solutions. NANOSCALE 2020; 12:21497-21518. [PMID: 33094770 DOI: 10.1039/d0nr06271e] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
In recent years, nanomaterials and nanotechnology have emerged as vital factors in the medical field with a unique contribution to cancer medicine. Given the increasing number of cancer patients, it is necessarily required to develop innovative strategies and therapeutic modalities to tackle hypoxia, which forms a hallmark and great barrier in treating solid tumors. The present review details the challenges in nanotechnology-based hypoxia, targeting the strategies and solutions for better therapeutic performances. The interaction between hypoxia and tumor is firstly introduced. Then, we review the recently developed engineered nanomaterials towards multimodal hypoxia tumor therapies, including chemotherapy, radiotherapy, and sonodynamic treatment. In the next part, we summarize the nanotechnology-based strategies for overcoming hypoxia problems. Finally, current challenges and future directions are proposed for successfully overcoming the hypoxia tumor problems.
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Affiliation(s)
- Aravindkumar Sundaram
- Department of Orthopaedic Surgery, the Sixth Affiliated Hospital of Guangzhou Medical University, 511508 Qingyuan, Guangdong, China.
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Jeong J, Taasti VT, Jackson A, Deasy JO. The relative biological effectiveness of carbon ion radiation therapy for early stage lung cancer. Radiother Oncol 2020; 153:265-271. [PMID: 32976878 DOI: 10.1016/j.radonc.2020.09.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/26/2020] [Accepted: 09/13/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND PURPOSE Carbon ion radiation therapy (CIRT) is recognized as an effective alternative treatment modality for early stage lung cancer, but a quantitative understanding of relative biological effectiveness (RBE) compared to photon therapy is lacking. In this work, a mechanistic tumor response model previously validated for lung photon radiotherapy was used to estimate the RBE of CIRT compared to photon radiotherapy, as a function of dose and the fractionation schedule. MATERIALS AND METHODS Clinical outcome data of 9 patient cohorts (394 patients) treated with CIRT for early stage lung cancer, representing all published data, were included. Fractional dose, number of fractions, treatment schedule, and local control rates were used for model simulations relative to standard photon outcomes. Four parameters were fitted: α, α/β, and the oxygen enhancement ratios of cells either accessing only glucose, not oxygen (OERI), or cells dying from starvation (OERH). The resulting dose-response relationship of CIRT was compared with the previously determined dose-response relationship of photon radiotherapy for lung cancer, and an RBE of CIRT was derived. RESULTS Best-fit CIRT parameters were: α = 1.12 Gy-1 [95%-CI: 0.97-1.26], α/β = 23.9 Gy [95%-CI: 8.9-38.9], and the oxygen induced radioresistance of hypoxic cell populations were characterized by OERI = 1.08 [95%-CI: 1.00-1.41] (cells lacking oxygen but not glucose), and OERH = 1.01 [95%-CI: 1.00-1.44] (cells lacking oxygen and glucose). Depending on dose and fractionation, the derived RBE ranges from 2.1 to 1.5, with decreasing values for larger fractional dose and fewer number of fractions. CONCLUSION Fitted radiobiological parameters were consistent with known carbon in vitro radiobiology, and the resulting dose-response curve well-fitted the reported data over a wide range of dose-fractionation schemes. The same model, with only a few fitted parameters of clear mechanistic meaning, thus synthesizes both photon radiotherapy and CIRT clinical experience with early stage lung tumors.
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Affiliation(s)
- Jeho Jeong
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, USA.
| | - Vicki T Taasti
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Andrew Jackson
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Joseph O Deasy
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, USA
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Reuvers TGA, Kanaar R, Nonnekens J. DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage. Cancers (Basel) 2020; 12:E2098. [PMID: 32731592 PMCID: PMC7463878 DOI: 10.3390/cancers12082098] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/24/2020] [Accepted: 07/26/2020] [Indexed: 12/11/2022] Open
Abstract
DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.
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Affiliation(s)
- Thom G. A. Reuvers
- Department of Molecular Genetics, Erasmus MC, Dr. Molenwaterplein 40, 3015 GD Rotterdam, The Netherlands; (T.G.A.R.); (R.K.)
- Department of Radiology and Nuclear Medicine, Erasmus MC, Dr. Molenwaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Roland Kanaar
- Department of Molecular Genetics, Erasmus MC, Dr. Molenwaterplein 40, 3015 GD Rotterdam, The Netherlands; (T.G.A.R.); (R.K.)
- Oncode Institute, Office Jaarbeurs Innovation Mile (JIM), Jaarbeursplein 6, 3561 AL Utrecht, The Netherlands
| | - Julie Nonnekens
- Department of Molecular Genetics, Erasmus MC, Dr. Molenwaterplein 40, 3015 GD Rotterdam, The Netherlands; (T.G.A.R.); (R.K.)
- Department of Radiology and Nuclear Medicine, Erasmus MC, Dr. Molenwaterplein 40, 3015 GD Rotterdam, The Netherlands
- Oncode Institute, Office Jaarbeurs Innovation Mile (JIM), Jaarbeursplein 6, 3561 AL Utrecht, The Netherlands
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Selemon LD, Begovic A. Reduced Midbrain Dopamine Neuron Number in the Adult Non-human Primate Brain after Fetal Radiation Exposure. Neuroscience 2020; 442:193-201. [PMID: 32659340 DOI: 10.1016/j.neuroscience.2020.07.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 06/17/2020] [Accepted: 07/02/2020] [Indexed: 11/19/2022]
Abstract
Early gestation is a neurodevelopmental period that is especially vulnerable to environmental insult and one in which neurogenesis features prominently. Prenatal perturbation during early gestation has been linked to neuropsychiatric illnesses such as autism and schizophrenia, and severe environmental insult during this period can result in profound mental impairment. Midbrain dopamine neurons are generated during early gestation and play a key role in the motor, cognitive and reward circuitries implicated in neuropsychiatric disease and addiction. This study examined the impact of curtailing neurogenesis in early gestation on neuron number in the midbrain dopamine group, i.e., the substantia nigra and contiguous ventral tegmental area. Rhesus macaque monkeys were exposed in utero on embryonic days 39-41 to x-irradiation (3-4 exposures of 50 cGy over 3-7 days totalling <200 cGy) and allowed to mature to full adulthood. Stereologic cell counts of tyrosine hydroxylase-positive neurons in the midbrain dopamine group were performed in adult monkeys, as were measurements of somal size. Mean total neuron number in the irradiated monkeys was significantly reduced on average by 33% compared to that of the control group. Somal size did not differ between the groups, suggesting that the integrity of survivor populations was not impacted. Reduced midbrain dopamine neuron number in fetally irradiated, adult monkeys indicates that radiation exposure during the critical period of neurogenesis results in an enduring reduction of this population and underscores the susceptibility of early neurodevelopmental processes to irreversible damage from environmental exposures.
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Affiliation(s)
- Lynn D Selemon
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States.
| | - Anita Begovic
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States
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Stage-Specific Effects of Ionizing Radiation during Early Development. Int J Mol Sci 2020; 21:ijms21113975. [PMID: 32492918 PMCID: PMC7312565 DOI: 10.3390/ijms21113975] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 05/28/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
Early embryonic cells are sensitive to genotoxic stressors such as ionizing radiation. However, sensitivity to these stressors varies depending on the embryonic stage. Recently, the sensitivity and response to ionizing radiation were found to differ during the preimplantation period. The cellular and molecular mechanisms underlying the change during this period are beginning to be elucidated. In this review, we focus on the changes in radio-sensitivity and responses to ionizing radiation during the early developmental stages of the preimplantation (before gastrulation) period in mammals, Xenopus, and fish. Furthermore, we discuss the underlying cellular and molecular mechanisms and the similarities and differences between species.
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35
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Calvaruso M, Pucci G, Musso R, Bravatà V, Cammarata FP, Russo G, Forte GI, Minafra L. Nutraceutical Compounds as Sensitizers for Cancer Treatment in Radiation Therapy. Int J Mol Sci 2019; 20:ijms20215267. [PMID: 31652849 PMCID: PMC6861933 DOI: 10.3390/ijms20215267] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 10/18/2019] [Accepted: 10/22/2019] [Indexed: 02/05/2023] Open
Abstract
The improvement of diagnostic techniques and the efficacy of new therapies in clinical practice have allowed cancer patients to reach a higher chance to be cured together with a better quality of life. However, tumors still represent the second leading cause of death worldwide. On the contrary, chemotherapy and radiotherapy (RT) still lack treatment plans which take into account the biological features of tumors and depend on this for their response to treatment. Tumor cells' response to RT is strictly-connected to their radiosensitivity, namely, their ability to resist and to overcome cell damage induced by ionizing radiation (IR). For this reason, radiobiological research is focusing on the ability of chemical compounds to radiosensitize cancer cells so to make them more responsive to IR. In recent years, the interests of researchers have been focused on natural compounds that show antitumoral effects with limited collateral issues. Moreover, nutraceuticals are easy to recover and are thus less expensive. On these bases, several scientific projects have aimed to test also their ability to induce tumor radiosensitization both in vitro and in vivo. The goal of this review is to describe what is known about the role of nutraceuticals in radiotherapy, their use and their potential application.
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Affiliation(s)
- Marco Calvaruso
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
| | - Gaia Pucci
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
| | - Rosa Musso
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
| | - Valentina Bravatà
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
| | - Francesco P Cammarata
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
| | - Giorgio Russo
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
| | - Giusi I Forte
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
| | - Luigi Minafra
- Istituto di Bioimmagini e Fisiologia Molecolare-Consiglio Nazionale delle Ricerche (IBFM-CNR), 90015 Cefalù (PA), Italy.
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Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-κB Pathway. Sci Rep 2019; 9:13284. [PMID: 31527721 PMCID: PMC6746859 DOI: 10.1038/s41598-019-49486-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 08/19/2019] [Indexed: 12/18/2022] Open
Abstract
Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Combination treatment showed the best tumour inhibition compared to that of orlistat alone or RT alone. These results suggest that prostate cancer treated by conventional RT could be improved by orlistat via inhibition of FASN.
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Lee ES, Kim JS, Lee H, Ryu JY, Lee HJ, Sonn JK, Lim YB. Auranofin, an Anti-rheumatic Gold Drug, Aggravates the Radiation-Induced Acute Intestinal Injury in Mice. Front Pharmacol 2019; 10:417. [PMID: 31105565 PMCID: PMC6492527 DOI: 10.3389/fphar.2019.00417] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/02/2019] [Indexed: 12/20/2022] Open
Abstract
Pelvic and abdominal radiotherapy plays an important role in eradication of malignant cells; however, it also results in slight intestinal injury. The apoptosis of cells in the intestinal epithelium is a primary pathological factor that initiates radiation-induced intestinal injury. Auranofin, a gold-containing triethylphosphine, was approved for the treatment of rheumatoid arthritis, and its therapeutic application has been expanded to a number of other diseases, such as parasitic infections, neurodegenerative disorders, AIDS, and bacterial infections. Recently, a treatment strategy combining the use of auranofin and ionizing radiation aimed at increasing the radiosensitivity of cancer cells was proposed for improving the control of local cancers. In this study, we evaluated the effect of auranofin on the radiosensitivity of intestinal epithelial cells. The treatment with a combination of 1 μM auranofin and 5 Gy ionizing radiation showed clear additive effects on caspase 3 cleavage and apoptotic DNA fragmentation in IEC-6 cells, and auranofin administration significantly aggravated the radiation-induced intestinal injury in mice. Auranofin treatment also resulted in the activation of the unfolded protein response and in the inhibition of thioredoxin reductase, which is a key component of the cellular antioxidant system. Pre-treatment with N-acetyl cysteine, a well-known scavenger of reactive oxygen species, but not with a chemical chaperone, which inhibits endoplasmic reticulum stress and the ensuing unfolded protein response, significantly reduced the radiosensitizing effects of auranofin in the IEC-6 cells. In addition, transfection of IEC-6 cells with a small interfering RNA targeted against thioredoxin reductase significantly enhanced the radiosensitivity of these cells. These results suggest that auranofin-induced radiosensitization of intestinal epithelial cells is mediated through oxidative stress caused by the deregulation of thioredoxin redox system, and auranofin treatment can be an independent risk factor for the development of acute pelvic radiation disease.
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Affiliation(s)
- Eun Sang Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Joong Sun Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Daejeon, South Korea
| | - Hyounji Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Jee-Yeon Ryu
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Hae-June Lee
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
| | - Jong Kyung Sonn
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea
| | - Young-Bin Lim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
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38
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Post AEM, Bussink J, Sweep FCGJ, Span PN. Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer. Oncol Res 2019; 28:33-40. [PMID: 31046897 PMCID: PMC7851527 DOI: 10.3727/096504019x15555794826018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.
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Affiliation(s)
- Annemarie E M Post
- Radboud University Medical Center, Department of Radiation Oncology, Radiotherapy and OncoImmunology LaboratoryNijmegenThe Netherlands
| | - Johan Bussink
- Radboud University Medical Center, Department of Radiation Oncology, Radiotherapy and OncoImmunology LaboratoryNijmegenThe Netherlands
| | - Fred C G J Sweep
- Radboud University Medical Center, Department of Laboratory MedicineNijmegenThe Netherlands
| | - Paul N Span
- Radboud University Medical Center, Department of Radiation Oncology, Radiotherapy and OncoImmunology LaboratoryNijmegenThe Netherlands
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Brzozowska B, Gałecki M, Tartas A, Ginter J, Kaźmierczak U, Lundholm L. Freeware tool for analysing numbers and sizes of cell colonies. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2019; 58:109-117. [PMID: 30673853 PMCID: PMC6394662 DOI: 10.1007/s00411-018-00772-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/18/2018] [Indexed: 05/22/2023]
Abstract
The clonogenic cell survival assay is a basic method to study the cytotoxic effect of radiation and chemical toxins. In large experimental setups, counting of colonies by eye is tiresome and prone to bias. Moreover, it is often interesting to quantify the size of individual colonies. Such analyses are largely facilitated by computerised image analysis systems. Although a number of such systems exist, they all focus on enumerating colonies and not on analysing the colony size. We have developed a new software package for both counting colonies and plotting their size distributions. The software called count and Plot HIstograms of Colony Size (countPHICS) consists of two parts: (1) a macro written for ImageJ which analyses computerised images of cell culture dishes or 6-well plates, counts colonies, estimates their size and saves the results in a text file; (2) a program written with QT Creator which reads the text file, plots histograms of colony size distribution and fits the best function. The full program is freely available at: http://www.fuw.edu.pl/~bbrzozow/FizMed/countPHICS.html . In conclusion, our new publically available software will facilitate colony counting and provide additional information on the colony growth rate, which is relevant especially for radiosensitisation studies.
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Affiliation(s)
- Beata Brzozowska
- Department of Molecular Biosciences, Centre for Radiation Protection Research, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
- Biomedical Physics Division, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 5 Pasteura Street, 106 91, Warsaw, Poland.
| | - Maciej Gałecki
- Biomedical Physics Division, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 5 Pasteura Street, 106 91, Warsaw, Poland
| | - Adrianna Tartas
- Biomedical Physics Division, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 5 Pasteura Street, 106 91, Warsaw, Poland
| | - Józef Ginter
- Biomedical Physics Division, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, 5 Pasteura Street, 106 91, Warsaw, Poland
| | | | - Lovisa Lundholm
- Department of Molecular Biosciences, Centre for Radiation Protection Research, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
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40
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Chen WK, Chen CA, Chi CW, Li LH, Lin CP, Shieh HR, Hsu ML, Ko CC, Hwang JJ, Chen YJ. Moscatilin Inhibits Growth of Human Esophageal Cancer Xenograft and Sensitizes Cancer Cells to Radiotherapy. J Clin Med 2019; 8:jcm8020187. [PMID: 30764514 PMCID: PMC6406854 DOI: 10.3390/jcm8020187] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/20/2019] [Accepted: 01/28/2019] [Indexed: 01/27/2023] Open
Abstract
Esophageal cancer prognosis remains poor in current clinical practice. We previously reported that moscatilin can induce apoptosis and mitotic catastrophe in esophageal cancer cells, accompanied by upregulation of polo-like kinase 1 (Plk1) expression. We aimed to validate in vitro activity and Plk1 expression in vivo following moscatilin treatment and to examine the treatment's radiosensitizing effect. Human esophageal cancer cells were implanted in nude mice. Moscatilin was intraperitoneally (i.p.) injected into the mice. Tumor size, body weight, white blood cell counts, and liver and renal function were measured. Aberrant mitosis and Plk1 expression were assessed. Colony formation was used to measure survival fraction after radiation. Moscatilin significantly suppressed tumor growth in mice bearing human esophageal xenografts without affecting body weight, white blood cell counts, or liver and renal function. Moscatilin also induced aberrant mitosis and apoptosis. Plk1 expression was markedly upregulated in vivo. Moreover, moscatilin pretreatment enhanced CE81T/VGH and BE3 cell radioresponse in vitro. Moscatilin may inhibit growth of human esophageal tumors and sensitize esophageal cancer cells to radiation therapy.
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Affiliation(s)
- Wun-Ke Chen
- Department of Radiation Oncology, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan.
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
| | - Chien-An Chen
- Department of Radiation Oncology in Zhongxing Branch, Taipei City Hospital, Taipei 10341, Taiwan.
| | - Chih-Wen Chi
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan.
- Department of Nursing, MacKay Medical College, New Taipei City 25245, Taiwan.
| | - Li-Hui Li
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan.
| | - Chin-Ping Lin
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan.
| | - Hui-Ru Shieh
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan.
| | - Ming-Ling Hsu
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan.
| | - Chun-Chuan Ko
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan.
| | - Jeng-Jong Hwang
- Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
| | - Yu-Jen Chen
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan.
- Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan.
- Department of Radiation Oncology, MacKay Memorial Hospital, Taipei 10449, Taiwan.
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Forshaw TE, Holmila R, Nelson KJ, Lewis JE, Kemp ML, Tsang AW, Poole LB, Lowther WT, Furdui CM. Peroxiredoxins in Cancer and Response to Radiation Therapies. Antioxidants (Basel) 2019; 8:antiox8010011. [PMID: 30609657 PMCID: PMC6356878 DOI: 10.3390/antiox8010011] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 12/23/2018] [Accepted: 12/25/2018] [Indexed: 12/11/2022] Open
Abstract
Peroxiredoxins have a long-established cellular function as regulators of redox metabolism by catalyzing the reduction of peroxides (e.g., H2O2, lipid peroxides) with high catalytic efficiency. This activity is also critical to the initiation and relay of both phosphorylation and redox signaling in a broad range of pathophysiological contexts. Under normal physiological conditions, peroxiredoxins protect normal cells from oxidative damage that could promote oncogenesis (e.g., environmental stressors). In cancer, higher expression level of peroxiredoxins has been associated with both tumor growth and resistance to radiation therapies. However, this relationship between the expression of peroxiredoxins and the response to radiation is not evident from an analysis of data in The Cancer Genome Atlas (TCGA) or NCI60 panel of cancer cell lines. The focus of this review is to summarize the current experimental knowledge implicating this class of proteins in cancer, and to provide a perspective on the value of targeting peroxiredoxins in the management of cancer. Potential biases in the analysis of the TCGA data with respect to radiation resistance are also highlighted.
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Affiliation(s)
- Tom E Forshaw
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - Reetta Holmila
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - Kimberly J Nelson
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - Joshua E Lewis
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
| | - Melissa L Kemp
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
| | - Allen W Tsang
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - Leslie B Poole
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - W Todd Lowther
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
| | - Cristina M Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
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Matsuya Y, McMahon SJ, Tsutsumi K, Sasaki K, Okuyama G, Yoshii Y, Mori R, Oikawa J, Prise KM, Date H. Investigation of dose-rate effects and cell-cycle distribution under protracted exposure to ionizing radiation for various dose-rates. Sci Rep 2018; 8:8287. [PMID: 29844494 PMCID: PMC5974424 DOI: 10.1038/s41598-018-26556-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 05/04/2018] [Indexed: 01/04/2023] Open
Abstract
During exposure to ionizing radiation, sub-lethal damage repair (SLDR) competes with DNA damage induction in cultured cells. By virtue of SLDR, cell survival increases with decrease of dose-rate, so-called dose-rate effects (DREs). Here, we focused on a wide dose-rate range and investigated the change of cell-cycle distribution during X-ray protracted exposure and dose-response curves via hybrid analysis with a combination of in vitro experiments and mathematical modelling. In the course of flow-cytometric cell-cycle analysis and clonogenic assays, we found the following responses in CHO-K1 cells: (1) The fraction of cells in S phase gradually increases during 6 h exposure at 3.0 Gy/h, which leads to radio-resistance. (2) Slight cell accumulation in S and G2/M phases is observed after exposure at 6.0 Gy/h for more than 10 hours. This suggests that an increase of SLDR rate for cells in S phase during irradiation may be a reproducible factor to describe changes in the dose-response curve at dose-rates of 3.0 and 6.0 Gy/h. By re-evaluating cell survival for various dose-rates of 0.186-60.0 Gy/h considering experimental-based DNA content and SLDR, it is suggested that the change of S phase fraction during irradiation modulates the dose-response curve and is possibly responsible for some inverse DREs.
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Affiliation(s)
- Yusuke Matsuya
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Stephen J McMahon
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Kaori Tsutsumi
- Faculty of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Kohei Sasaki
- Faculty of Health Sciences, Hokkaido University of Science, Sapporo, 006-8585, Japan
| | - Go Okuyama
- Faculty of Health Sciences, Hokkaido University of Science, Sapporo, 006-8585, Japan
| | - Yuji Yoshii
- Biological Research, Education and Instrumentation Center, Sapporo Medical University, Sapporo, 060-8556, Japan
| | - Ryosuke Mori
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Joma Oikawa
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Kevin M Prise
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Hiroyuki Date
- Faculty of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
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Matsuya Y, McMahon SJ, Tsutsumi K, Sasaki K, Okuyama G, Yoshii Y, Mori R, Oikawa J, Prise KM, Date H. Investigation of dose-rate effects and cell-cycle distribution under protracted exposure to ionizing radiation for various dose-rates. Sci Rep 2018. [PMID: 29844494 DOI: 10.1038/s41598a018-26556a5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023] Open
Abstract
During exposure to ionizing radiation, sub-lethal damage repair (SLDR) competes with DNA damage induction in cultured cells. By virtue of SLDR, cell survival increases with decrease of dose-rate, so-called dose-rate effects (DREs). Here, we focused on a wide dose-rate range and investigated the change of cell-cycle distribution during X-ray protracted exposure and dose-response curves via hybrid analysis with a combination of in vitro experiments and mathematical modelling. In the course of flow-cytometric cell-cycle analysis and clonogenic assays, we found the following responses in CHO-K1 cells: (1) The fraction of cells in S phase gradually increases during 6 h exposure at 3.0 Gy/h, which leads to radio-resistance. (2) Slight cell accumulation in S and G2/M phases is observed after exposure at 6.0 Gy/h for more than 10 hours. This suggests that an increase of SLDR rate for cells in S phase during irradiation may be a reproducible factor to describe changes in the dose-response curve at dose-rates of 3.0 and 6.0 Gy/h. By re-evaluating cell survival for various dose-rates of 0.186-60.0 Gy/h considering experimental-based DNA content and SLDR, it is suggested that the change of S phase fraction during irradiation modulates the dose-response curve and is possibly responsible for some inverse DREs.
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Affiliation(s)
- Yusuke Matsuya
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Stephen J McMahon
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Kaori Tsutsumi
- Faculty of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Kohei Sasaki
- Faculty of Health Sciences, Hokkaido University of Science, Sapporo, 006-8585, Japan
| | - Go Okuyama
- Faculty of Health Sciences, Hokkaido University of Science, Sapporo, 006-8585, Japan
| | - Yuji Yoshii
- Biological Research, Education and Instrumentation Center, Sapporo Medical University, Sapporo, 060-8556, Japan
| | - Ryosuke Mori
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Joma Oikawa
- Graduate School of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Kevin M Prise
- Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Hiroyuki Date
- Faculty of Health Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
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Mori R, Matsuya Y, Yoshii Y, Date H. Estimation of the radiation-induced DNA double-strand breaks number by considering cell cycle and absorbed dose per cell nucleus. JOURNAL OF RADIATION RESEARCH 2018; 59:253-260. [PMID: 29800455 PMCID: PMC5967466 DOI: 10.1093/jrr/rrx097] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Indexed: 05/06/2023]
Abstract
DNA double-strand breaks (DSBs) are thought to be the main cause of cell death after irradiation. In this study, we estimated the probability distribution of the number of DSBs per cell nucleus by considering the DNA amount in a cell nucleus (which depends on the cell cycle) and the statistical variation in the energy imparted to the cell nucleus by X-ray irradiation. The probability estimation of DSB induction was made following these procedures: (i) making use of the Chinese Hamster Ovary (CHO)-K1 cell line as the target example, the amounts of DNA per nucleus in the logarithmic and the plateau phases of the growth curve were measured by flow cytometry with propidium iodide (PI) dyeing; (ii) the probability distribution of the DSB number per cell nucleus for each phase after irradiation with 1.0 Gy of 200 kVp X-rays was measured by means of γ-H2AX immunofluorescent staining; (iii) the distribution of the cell-specific energy deposition via secondary electrons produced by the incident X-rays was calculated by WLTrack (in-house Monte Carlo code); (iv) according to a mathematical model for estimating the DSB number per nucleus, we deduced the induction probability density of DSBs based on the measured DNA amount (depending on the cell cycle) and the calculated dose per nucleus. The model exhibited DSB induction probabilities in good agreement with the experimental results for the two phases, suggesting that the DNA amount (depending on the cell cycle) and the statistical variation in the local energy deposition are essential for estimating the DSB induction probability after X-ray exposure.
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Affiliation(s)
- Ryosuke Mori
- Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo 060-0812, Japan
| | - Yusuke Matsuya
- Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo 060-0812, Japan
| | - Yuji Yoshii
- Biological Research, Education and Instrumentation Center, Sapporo Medical University, Minami-1, Nichi-17, Chuo-ku, Sapporo 060-8556, Japan
| | - Hiroyuki Date
- Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo 060-812, Japan
- Corresponding author. Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo 060-812, Japan. Tel: +81-11-706-3423; Fax: +81-11-706-4916;
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Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure. Int J Mol Sci 2018; 19:ijms19020496. [PMID: 29414878 PMCID: PMC5855718 DOI: 10.3390/ijms19020496] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 01/29/2018] [Accepted: 02/02/2018] [Indexed: 12/25/2022] Open
Abstract
Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.
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Matsuya Y, Kimura T, Date H. Markov chain Monte Carlo analysis for the selection of a cell-killing model under high-dose-rate irradiation. Med Phys 2017; 44:5522-5532. [PMID: 28786486 DOI: 10.1002/mp.12508] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 07/04/2017] [Accepted: 07/27/2017] [Indexed: 12/19/2022] Open
Abstract
PURPOSE High-dose-rate irradiation with 6 MV linac x rays is a wide-spread means to treat cancer tissue in radiotherapy. The treatment planning relies on a mathematical description of surviving fraction (SF), such as the linear-quadratic model (LQM) formula. However, even in the case of high-dose-rate treatment, the repair kinetics of DNA damage during dose-delivery time plays a function in predicting the dose-SF relation. This may call the SF model selection into question when considering the dose-delivery time or dose-rate effects (DREs) in radiotherapy and in vitro cell experiments. In this study, we demonstrate the importance of dose-delivery time at high-dose-rate irradiations used in radiotherapy by means of Bayesian estimation. METHODS To evaluate the model selection for SF, three types of models, the LQM and two microdosimetric-kinetic models with and without DREs (MKMDR and MKM) were applied to describe in vitroSF data (our work and references). The parameters in each model were evaluated by a Markov chain Monte Carlo (MCMC) simulation. RESULTS The MCMC analysis shows that the cell survival curve by the MKMDR fits the experimental data the best in terms of the deviance information criterion (DIC). In the fractionated regimen with 30 fractions to a total dose of 60 Gy, the final cell survival estimated by the MKMDR was higher than that by the LQM. This suggests that additional fractions are required for attaining the total dose equivalent to yield the same effect as the conventional regimen using the LQM in fractionated radiotherapy. CONCLUSIONS Damage repair during dose-delivery time plays a key role in precisely estimating cell survival even at a high dose rate in radiotherapy. Consequently, it was suggested that the cell-killing model without repair factor during a short dose-delivery time may overestimate actual cell killing in fractionated radiotherapy.
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Affiliation(s)
- Yusuke Matsuya
- Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku,, Sapporo, 060-0812, Japan
| | - Takaaki Kimura
- Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku,, Sapporo, 060-0812, Japan
| | - Hiroyuki Date
- Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku,, Sapporo, 060-0812, Japan
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Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2. Oncogene 2017; 37:52-62. [DOI: 10.1038/onc.2017.304] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Revised: 06/29/2017] [Accepted: 07/20/2017] [Indexed: 12/13/2022]
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Goto Y, Koyasu S, Kobayashi M, Harada H. The emerging roles of the ubiquitination/deubiquitination system in tumor radioresistance regarding DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties: Insight into the development of novel radiosensitizing strategies. Mutat Res 2017; 803-805:76-81. [PMID: 28778421 DOI: 10.1016/j.mrfmmm.2017.07.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 07/02/2017] [Accepted: 07/17/2017] [Indexed: 10/19/2022]
Abstract
Radiation therapy is one of the first-line treatments for many cancers, with no less than half of cancer patients receiving it in the US. Despite the development of innovative and high-precision radiation therapy strategies, many patients still experience local tumor recurrence after the treatment, at least in part, due to the existence of radioresistant cells in malignant tumor tissues. Among the various biological processes known to induce radioresistance, a post-translational protein modification, ubiquitination, has received marked attention in recent years. Ubiquitination, in which highly conserved ubiquitin polypeptides are covalently attached to their target proteins, has long been recognized as a system to tag unnecessary proteins for 26S proteasome-dependent proteolysis. However, accumulating lines of evidence recently revealed that it acts as a signal molecule in diverse biological processes as well, and its functional disorder was found to cause not only tumor development and various diseases but also tumor radioresistance. The present review summarizes the latest knowledge about how the cancer-related disorder of the ubiquitination systems induces the radioresistance of cancer cells by influencing intrinsic pathways, each of which potentially affects the radioresistance/radiosensitivity of cells, such as DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties. In addition, this review aims to provide insights into how we can exploit the disorders in order to develop novel radiosensitizing strategies.
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Affiliation(s)
- Yoko Goto
- Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Sho Koyasu
- Laboratory of Cancer Cell Biology, Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Applied Chemistry, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Minoru Kobayashi
- Laboratory of Cancer Cell Biology, Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Hiroshi Harada
- Laboratory of Cancer Cell Biology, Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
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Jeong J, Oh JH, Sonke JJ, Belderbos J, Bradley JD, Fontanella AN, Rao SS, Deasy JO. Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules. Clin Cancer Res 2017; 23:5469-5479. [PMID: 28539466 DOI: 10.1158/1078-0432.ccr-16-3277] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 04/17/2017] [Accepted: 05/16/2017] [Indexed: 12/25/2022]
Abstract
Purpose: To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy and to predict the likelihood of local control as a function of dose and treatment fractions.Experimental Design: We model outcomes for early-stage, localized non-small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and two unpublished early-stage patient cohorts, totaling 2,701 patients.Results: Precise likelihood best-fit values were derived for the radiobiological parameters: α [0.305 Gy-1; 95% confidence interval (CI), 0.120-0.365], the α/β ratio (2.80 Gy; 95% CI, 0.40-4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI, 1.55-2.25). All fractionation groups are well fitted by a single dose-response curve with a high χ2 P value, indicating consistency with the fitted model. The analysis was further validated with an additional 23 patient cohorts (n = 1,628). The model indicates that hypofractionation regimens overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimens allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation.Conclusions: This proposed mechanistic tumor-response model can accurately predict overtreatment or undertreatment for various treatment regimens. Clin Cancer Res; 23(18); 5469-79. ©2017 AACR.
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Affiliation(s)
- Jeho Jeong
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Jung Hun Oh
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jan-Jakob Sonke
- Department of Radiation Oncology, The Netherlands Cancer Institute, Postbus, Amsterdam, the Netherlands
| | - Jose Belderbos
- Department of Radiation Oncology, The Netherlands Cancer Institute, Postbus, Amsterdam, the Netherlands
| | - Jeffrey D Bradley
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Andrew N Fontanella
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shyam S Rao
- Department of Radiation Oncology, University of California, Davis Comprehensive Cancer Center, Sacramento, California
| | - Joseph O Deasy
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
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