{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T04:04:09Z","timestamp":1768277049824,"version":"3.49.0"},"reference-count":67,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T00:00:00Z","timestamp":1664755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002661","name":"Belgian Fonds National de la Recherche Scientifique","doi-asserted-by":"publisher","award":["J008220F"],"award-info":[{"award-number":["J008220F"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002661","name":"Belgian Fonds National de la Recherche Scientifique","doi-asserted-by":"publisher","award":["ARC 21-26\/118"],"award-info":[{"award-number":["ARC 21-26\/118"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Actions de Recherche Concert\u00e9es program of the Communaut\u00e9 Fran\u00e7aise de Belgique","award":["J008220F"],"award-info":[{"award-number":["J008220F"]}]},{"name":"Actions de Recherche Concert\u00e9es program of the Communaut\u00e9 Fran\u00e7aise de Belgique","award":["ARC 21-26\/118"],"award-info":[{"award-number":["ARC 21-26\/118"]}]},{"name":"Nuclear and Electron Spin Technologies platform","award":["J008220F"],"award-info":[{"award-number":["J008220F"]}]},{"name":"Nuclear and Electron Spin Technologies platform","award":["ARC 21-26\/118"],"award-info":[{"award-number":["ARC 21-26\/118"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors. Methods: OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO2 was measured in vivo using low-frequency EPR oximetry to define the optimal window of reoxygenation, the time at which tumors were irradiated with a single 6 Gy dose with a Cesium-137 irradiator. Results: 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg\/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT. Conclusions: exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation.<\/jats:p>","DOI":"10.3390\/biom12101418","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T00:07:43Z","timestamp":1665187663000},"page":"1418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Statins Alleviate Tumor Hypoxia in Prostate Cancer Models by Decreasing Oxygen Consumption: An Opportunity for Radiosensitization?"],"prefix":"10.3390","volume":"12","author":[{"given":"Donatienne","family":"d\u2019Hose","sequence":"first","affiliation":[{"name":"Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Universit\u00e9 Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9426-8600","authenticated-orcid":false,"given":"Lionel","family":"Mignion","sequence":"additional","affiliation":[{"name":"Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Universit\u00e9 Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lo\u00efc","family":"Hamelin","sequence":"additional","affiliation":[{"name":"Pole of Pharmacology and Therapeutics, Institut de Recherches Exp\u00e9rimentales et Cliniques (IREC), Universit\u00e9 Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-8834","authenticated-orcid":false,"given":"Pierre","family":"Sonveaux","sequence":"additional","affiliation":[{"name":"Pole of Pharmacology and Therapeutics, Institut de Recherches Exp\u00e9rimentales et Cliniques (IREC), Universit\u00e9 Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium"},{"name":"Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Research Institute, 1300 Wavre, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7126-2206","authenticated-orcid":false,"given":"B\u00e9n\u00e9dicte F.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Universit\u00e9 Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5708-1302","authenticated-orcid":false,"given":"Bernard","family":"Gallez","sequence":"additional","affiliation":[{"name":"Biomedical Magnetic Resonance, Louvain Drug Research Institute (LDRI), Universit\u00e9 Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.3389\/fchem.2020.00516","article-title":"The Innovative Potential of Statins in Cancer: New Targets for New Therapies","volume":"8","author":"Zwergel","year":"2020","journal-title":"Front. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111858","DOI":"10.1016\/j.biopha.2021.111858","article-title":"The potential use of simvastatin for cancer treatment: A review","volume":"141","author":"Duarte","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_3","first-page":"717","article-title":"Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis","volume":"12","author":"Bockhorn","year":"1998","journal-title":"Int. J. Oncol."},{"key":"ref_4","first-page":"1149","article-title":"Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin","volume":"24","author":"Katarzyna","year":"2004","journal-title":"Int. J. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1038\/sj.onc.1209117","article-title":"Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling","volume":"25","author":"Khanzada","year":"2006","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.semcancer.2020.08.002","article-title":"Effects of statins on brain tumors: A review","volume":"73","author":"Afshari","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1053\/j.gastro.2017.05.011","article-title":"Statin Use after Diagnosis of Colon Cancer and Patient Survival","volume":"153","author":"Voorneveld","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"BSR20200232","DOI":"10.1042\/BSR20200232","article-title":"Statin use and the prognosis of patients with hepatocellular carcinoma: A meta-analysis","volume":"40","author":"Li","year":"2020","journal-title":"Biosci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.jgo.2019.01.011","article-title":"Survival benefit of statins in older patients with rectal cancer: A Swedish population-based cohort study","volume":"10","author":"Kotti","year":"2019","journal-title":"J. Geriatr. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.oraloncology.2019.01.019","article-title":"Statin use associated with improved overall and cancer specific survival in patients with head and neck cancer","volume":"90","author":"Gupta","year":"2019","journal-title":"Oral Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"405","DOI":"10.2147\/DDDT.S187690","article-title":"Statin use and prognosis of lung cancer: A systematic review and meta-analysis of observational studies and randomized controlled trials","volume":"13","author":"Xia","year":"2019","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.canep.2017.04.015","article-title":"Statin use after esophageal cancer diagnosis and survival: A population based cohort study","volume":"48","author":"Cardwell","year":"2017","journal-title":"Cancer Epidemiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1038\/bjc.2017.139","article-title":"Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study","volume":"116","author":"Gray","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1200\/JCO.2016.69.7391","article-title":"Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR)","volume":"35","author":"Seckl","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.ijrobp.2009.12.006","article-title":"Improved biochemical outcomes with statin use in patients with high-risk localized prostate cancer treated with radiotherapy","volume":"79","author":"Kollmeier","year":"2011","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_16","first-page":"298","article-title":"Statins, especially atorvastatin, may improve survival following brachytherapy for clinically localized prostate cancer","volume":"26","author":"Moyad","year":"2006","journal-title":"Urol. Nurs."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00345-014-1281-x","article-title":"Statin use is associated with decreased prostate cancer recurrence in men treated with brachytherapy","volume":"33","author":"Oh","year":"2015","journal-title":"World J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1093\/annonc\/mdt077","article-title":"Statins and prostate cancer recurrence following radical prostatectomy or radiotherapy: A systematic review and meta-analysis","volume":"24","author":"Park","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"BSR20170340","DOI":"10.1042\/BSR20170340","article-title":"Atorvastatin enhances radiosensitivity in hypoxia-induced prostate cancer cells related with HIF-1\u03b1 inhibition","volume":"37","author":"Chen","year":"2017","journal-title":"Biosci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1053\/j.semnuclmed.2014.11.002","article-title":"The clinical significance of hypoxia in human cancers","volume":"45","author":"Dhani","year":"2015","journal-title":"Semin. Nucl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1089\/ars.2013.5378","article-title":"The clinical importance of assessing tumor hypoxia: Relationship of tumor hypoxia to prognosis and therapeutic opportunities","volume":"21","author":"Walsh","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fonc.2017.00010","article-title":"Assessing Tumor Oxygenation for Predicting Outcome in Radiation Oncology: A Review of Studies Correlating Tumor Hypoxic Status and Outcome in the Preclinical and Clinical Settings","volume":"7","author":"Colliez","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0093-7754(01)90210-6","article-title":"Oxygen status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy","volume":"28","author":"Vaupel","year":"2001","journal-title":"Semin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.semradonc.2004.04.008","article-title":"Tumor microenvironmental physiology and its implications for radiation oncology","volume":"14","author":"Vaupel","year":"2004","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Joiner, M., and van der Kogel, A. (2009). The oxygen effect and fractionated radiotherapy. Basic Clinical Radiobiology, Hodder Arnold. [4th ed.].","DOI":"10.1201\/b15450"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"313","DOI":"10.3109\/02841869509093981","article-title":"Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors","volume":"34","author":"Secomb","year":"1995","journal-title":"Acta Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1158\/0008-5472.CAN-11-1755","article-title":"Arsenic trioxide treatment decreases the oxygen consumption rate of tumor cells and radiosensitizes solid tumors","volume":"72","author":"Diepart","year":"2012","journal-title":"Cancer Res."},{"key":"ref_28","first-page":"3555","article-title":"Insulin increases the sensitivity of tumors to irradiation: Involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption","volume":"62","author":"Jordan","year":"2002","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1158\/1078-0432.CCR-06-0802","article-title":"Glucocorticoids modulate tumor radiation response through a decrease in tumor oxygen consumption","volume":"13","author":"Crokart","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12308","DOI":"10.1038\/ncomms12308","article-title":"The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia","volume":"7","author":"Ashton","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6741","DOI":"10.1158\/1078-0432.CCR-13-1787","article-title":"Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response","volume":"19","author":"Zannella","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1158\/1535-7163.MCT-15-0691-T","article-title":"A Fast Hydrogen Sulfide-Releasing Donor Increases the Tumor Response to Radiotherapy","volume":"15","author":"Deriemaeker","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.bbabio.2017.01.002","article-title":"Manipulation of tumor oxygenation and radiosensitivity through modification of cell respiration. A critical review of approaches and imaging biomarkers for therapeutic guidance","volume":"1858","author":"Gallez","year":"2017","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00204-014-1378-4","article-title":"Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo","volume":"90","author":"Bonifacio","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.freeradbiomed.2011.10.449","article-title":"Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes","volume":"52","author":"Kwak","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_36","first-page":"365","article-title":"Influence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in rat liver during ischemia","volume":"270","author":"Satoh","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_37","first-page":"2009","article-title":"In vivo oxygen consumption rate of DS sarcoma cells on inhibition of DNA synthesis","volume":"56","author":"Thews","year":"1996","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.drudis.2007.12.008","article-title":"Advances in measuring cellular bioenergetics using extracellular flux","volume":"13","author":"Ferrick","year":"2008","journal-title":"Drug Discov. Today"},{"key":"ref_39","first-page":"41","article-title":"Statin-mediated reduction of osteopontin expression induces apoptosis and cell growth arrest in ovarian clear cell carcinoma","volume":"25","author":"Matsuura","year":"2011","journal-title":"Oncol. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Goc, A., Kochuparambil, S.T., Al-Husein, B., Al-Azayzih, A., Mohammad, S., and Somanath, P.R. (2012). Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-409"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.3892\/ijo.2013.2126","article-title":"Simvastatin reduces melanoma progression in a murine model","volume":"43","author":"Zanfardino","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/sj.bjc.6602720","article-title":"Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells","volume":"93","author":"Bocci","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.ab.2009.09.029","article-title":"Comparison of methods for measuring oxygen consumption in tumor cells in vitro","volume":"396","author":"Diepart","year":"2010","journal-title":"Anal. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"101852","DOI":"10.1016\/j.redox.2020.101852","article-title":"A versatile EPR toolbox for the simultaneous measurement of oxygen consumption and superoxide production","volume":"40","author":"Danhier","year":"2021","journal-title":"Redox Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1089\/ars.2012.4886","article-title":"Methods for Detection of Mitochondrial and Cellular Reactive Oxygen Species","volume":"20","author":"Dikalov","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"417","DOI":"10.3109\/10715762.2010.540242","article-title":"EPR detection of cellular and mitochondrial superoxide using cyclic hydroxylamines","volume":"45","author":"Dikalov","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s12013-020-00921-6","article-title":"An EPR Study Using Cyclic Hydroxylamines to Assess the Level of Mitochondrial ROS in Superinvasive Cancer Cells","volume":"78","author":"Scheinok","year":"2020","journal-title":"Cell Biochem. Biophys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6884","DOI":"10.1016\/S0021-9258(18)68727-7","article-title":"Superoxide dismutase and catalase conjugated to polyethylene glycol increases endothelial enzyme activity and oxidant resistance","volume":"263","author":"Beckman","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.mri.2004.02.005","article-title":"Effect of anesthesia on the signal intensity in tumors using BOLD-MRI: Comparison with flow measurements by Laser Doppler flowmetry and oxygen measurements by luminescence-based probes","volume":"22","author":"Baudelet","year":"2004","journal-title":"Magn. Reson. Imaging"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/(SICI)1522-2594(199910)42:4<627::AID-MRM2>3.0.CO;2-M","article-title":"Pharmacological modifications of the partial pressure of oxygen in murine tumors: Evaluation using in vivo EPR oximetry","volume":"42","author":"Gallez","year":"1999","journal-title":"Magn. Reson. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1002\/nbm.900","article-title":"Assessment of tumor oxygenation by electron paramagnetic resonance: Principles and applications","volume":"17","author":"Gallez","year":"2004","journal-title":"NMR Biomed."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e14541","DOI":"10.14814\/phy2.14541","article-title":"How best to interpret measures of levels of oxygen in tissues to make them effective clinical tools for care of patients with cancer and other oxygen-dependent pathologies","volume":"8","author":"Swartz","year":"2020","journal-title":"Physiol. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00723-021-01358-7","article-title":"Oxygenation Status in Normal Tissues, Pathological Tissues and Malignant Tumors: A pO2 Database Based on Electron Paramagnetic Resonance (EPR) Oximetry Measurements","volume":"52","author":"Gallez","year":"2021","journal-title":"Appl. Magn. Reson."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/BF02592236","article-title":"Carbon-centered radicals as oxygen sensors for in vivo electron paramagnetic resonance: Screening for an optimal probe among commercially available charcoals","volume":"7","author":"Jordan","year":"1998","journal-title":"Magn. Reson. Mater. Phys. Biol. Med."},{"key":"ref_55","unstructured":"Kallmann, R.F. (1987). Principles and practice of the tumor growth delay assay. Rodent Tumor Models in Experimental Cancer Therapy, Pergamon Press."},{"key":"ref_56","first-page":"1","article-title":"New anticancer agents: In vitro and in vivo evaluation","volume":"19","author":"Zips","year":"2005","journal-title":"In Vivo"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Jezek, J., Cooper, K.F., and Strich, R. (2018). Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression. Antioxidants, 7.","DOI":"10.3390\/antiox7010013"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.redox.2017.12.012","article-title":"Teaching the basics of reactive oxygen species and their relevance to cancer biology: Mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies","volume":"15","author":"Kalyanaraman","year":"2018","journal-title":"Redox Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1007\/s10637-020-01046-6","article-title":"Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture","volume":"39","author":"Manda","year":"2021","journal-title":"Investig. New Drugs"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"600","DOI":"10.3389\/fphar.2018.00600","article-title":"Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1007\/s00464-017-5841-1","article-title":"Simvastatin enhances radiation sensitivity of colorectal cancer cells","volume":"32","author":"Karagkounis","year":"2018","journal-title":"Surg. Endosc."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"III32","DOI":"10.1002\/clc.4960261507","article-title":"Pharmacologic characteristics of statins","volume":"26","author":"McKenney","year":"2003","journal-title":"Clin. Cardiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"104201","DOI":"10.1016\/j.phrs.2019.03.010","article-title":"Mechanisms of statin-associated skeletal muscle-associated symptoms","volume":"154","author":"Bouitbir","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Danhier, P., Copetti, T., De Preter, G., Leveque, P., Feron, O., Jordan, B.F., Sonveaux, P., and Gallez, B. (2013). Influence of cell detachment on the respiration rate of tumor and endothelial cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053324"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"126","DOI":"10.2307\/3575801","article-title":"A rapid-mixing comparison of the mechanisms of radiosensitization by oxygen and misonidazole in CHO cells","volume":"90","author":"Whillans","year":"1982","journal-title":"Radiat. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2307\/3576058","article-title":"The effect on the Km for radiosensitization at 0 degree C of thiol depletion by diethylmaleate pretreatment: Quantitative differences found using the radiation sensitizing agent misonidazole or oxygen","volume":"98","author":"Koch","year":"1984","journal-title":"Radiat. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1111\/j.1365-2125.2011.03907.x","article-title":"What is a relevant statin concentration in cell experiments claiming pleiotropic effects?","volume":"72","author":"Lindh","year":"2011","journal-title":"Br. J. Clin. Pharmacol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/10\/1418\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:46:05Z","timestamp":1760143565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/10\/1418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,3]]},"references-count":67,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["biom12101418"],"URL":"https:\/\/doi.org\/10.3390\/biom12101418","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,3]]}}}