Generic placeholder image

Current Clinical Pharmacology


ISSN (Print): 1574-8847
ISSN (Online): 2212-3938

Review Article

Metformin as a Radiation Modifier; Implications to Normal Tissue Protection and Tumor Sensitization

Author(s): Keywan Mortezaee, Dheyauldeen Shabeeb, Ahmed E. Musa, Masoud Najafi* and Bagher Farhood*

Volume 14, Issue 1, 2019

Page: [41 - 53] Pages: 13

DOI: 10.2174/1574884713666181025141559


Background: Nowadays, ionizing radiation is used for several applications in medicine, industry, agriculture, and nuclear power generation. Besides the beneficial roles of ionizing radiation, there are some concerns about accidental exposure to radioactive sources. The threat posed by its use in terrorism is of global concern. Furthermore, there are several side effects to normal organs for patients who had undergone radiation treatment for cancer. Hence, the modulation of radiation response in normal tissues was one of the most important aims of radiobiology. Although, so far, several agents have been investigated for protection and mitigation of radiation injury. Agents such as amifostine may lead to severe toxicity, while others may interfere with radiation therapy outcomes as a result of tumor protection. Metformin is a natural agent that is well known as an antidiabetic drug. It has shown some antioxidant effects and enhances DNA repair capacity, thereby ameliorating cell death following exposure to radiation. Moreover, through targeting endogenous ROS production within cells, it can mitigate radiation injury. This could potentially make it an effective radiation countermeasure. In contrast to other radioprotectors, metformin has shown modulatory effects through induction of several genes such as AMPK, which suppresses reduction/ oxidation (redox) reactions, protects cells from accumulation of unrepaired DNA, and attenuates initiation of inflammation as well as fibrotic pathways. Interestingly, these properties of metformin can sensitize cancer cells to radiotherapy.

Conclusion: In this article, we aimed to review the interesting properties of metformin such as radioprotection, radiomitigation and radiosensitization, which could make it an interesting adjuvant for clinical radiotherapy, as well as an interesting candidate for mitigation of radiation injury after a radiation disaster.

Keywords: Radiation, metformin, radioprotection, mitigation, radiosensitization, inflammation, redox, fibrosis, tumor hypoxia, DNA repair, mitochondria, AMPK, tumor resistance, cell cycle.

Graphical Abstract
Farhood B, Goradel NH, Mortezaee K, et al. Intercellular communications-redox interactions in radiation toxicity; potential targets for radiation mitigation. J Cell Commun Signal 2018. [Epub ahead of print].
Johnson SM, Torrice CD, Bell JF, et al. Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest 2010; 120: 2528-36.
Mahmood J, Jelveh S, Zaidi A, Doctrow SR, Medhora M, Hill RP. Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage. Int J Radiat Oncol Biol Phys 2014; 89: 722-8.
Medhora M, Gao F, Jacobs ER, Moulder JE. Radiation damage to the lung: Mitigation by Angiotensin-Converting Enzyme (ACE) inhibitors. Respirology 2012; 17: 66-71.
Moulder JE. Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review. Int J Radiat Biol 2004; 80: 3-10.
Narmani A, Farhood B, Haghi-Aminjan H, et al. Gadolinium nanoparticles as diagnostic and therapeutic agents: Their delivery systems in magnetic resonance imaging and neutron capture therapy. J Drug Deliv Sci Technol 2018; 44: 457-66.
Ghadjar P, Hayoz S, Bernhard J, et al. Acute toxicity and quality of life after dose-intensified salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: First results of the randomized trial SAKK 09/10. J Clin Oncol 2015; 33: 4158-66.
Goenka A, Magsanoc JM, Pei X, et al. Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy. Eur Urol 2011; 60: 1142-8.
Farhood B, Mortezaee K, Goradel NH, et al. Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy. J Cell Physiol 2019; 234(5): 5728-40.
Bagheri H, Rezapour S, Najafi M, et al. Protection against radiation-induced micronuclei in rat bone marrow erythrocytes by Curcumin and selenium L-methionine. Iran J Med Sci 2018; 43(6): 645-52.
Brown SL, Kolozsvary A, Liu J, Jenrow KA, Ryu S, Kim JH. Antioxidant diet supplementation starting 24 hours after exposure reduces radiation lethality. Radiat Res 2010; 173: 462-8.
Freytag SO, Movsas B, Aref I, et al. Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. Mol Ther 2007; 15: 1016-23.
Kuo P, Bratman SV, Shultz DB, et al. Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clin Cancer Res 2014; 20: 5558-69.
Standish LJ, Torkelson C, Hamill FA, et al. Immune defects in breast cancer patients after radiotherapy. J Soc Integr Oncol 2008; 6: 110-21.
Miljković MD, Grossman SA, Ye X, Ellsworth S, Terezakis S. Patterns of radiation-associated lymphopenia in children with cancer. Cancer Invest 2016; 34: 32-8.
Kou F, Lu Z, Li J, et al. Pretreatment lymphopenia is an easily detectable predictive and prognostic marker in patients with metastatic esophagus squamous cell carcinoma receiving first‐line chemotherapy. Cancer Med 2016; 5: 778-86.
Weiner JP, Wong AT, Schwartz D, Martinez M, Aytaman A, Schreiber D. Endoscopic and non-endoscopic approaches for the management of radiation-induced rectal bleeding. World J Gastroenterol 2016; 22: 6972-86.
Lenz L, Rohr R, Nakao F, Libera E, Ferrari A. Chronic radiation proctopathy: A practical review of endoscopic treatment. World J Gastrointest Surg 2016; 8: 151-60.
Hanson B, MacDonald R, Shaukat A. Endoscopic and medical therapy for chronic radiation proctopathy: A systematic review. Dis Colon Rectum 2012; 55: 1081-95.
van de Wetering FT, Verleye L, Andreyev HJ, et al. Non-surgical interventions for late rectal problems (proctopathy) of radiotherapy in people who have received radiotherapy to the pelvis. Cochrane Database Syst Rev 2016; 4: Cd003455.
Amini P, Mirtavoos-Mahyari H, Motevaseli E, et al. Mechanisms for radioprotection by melatonin; can it be used as a radiation countermeasure? Curr Mol Pharmacol 2019; 12(1): 2-11.
Gauter-Fleckenstein B, Fleckenstein K, Owzar K, et al. Early and late administration of MnTE-2-PyP 5+ in mitigation and treatment of radiation-induced lung damage. Free Radic Biol Med 2010; 48: 1034-43.
Medhora M, Haworth S, Liu Y, et al. Biomarkers for radiation pneumonitis using noninvasive molecular imaging. J Nucl Med 2016; 57: 1296-301.
Pietrofesa R, Turowski J, Tyagi S, et al. Radiation mitigating properties of the lignan component in flaxseed. BMC Cancer 2013; 13: 179.
Serin M, Gulbas H, Gurses I, Erkal HS, Yucel N. The histopathological evaluation of the effectiveness of melatonin as a protectant against acute lung injury induced by radiation therapy in a rat model. Int J Radiat Biol 2007; 83: 187-93.
Ward PA, Hunninghake GW. Lung inflammation and fibrosis. Am J Respir Crit Care Med 1998; 157: S123-9.
Zhao W, Robbins ME. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: Therapeutic implications. Curr Med Chem 2009; 16: 130-43.
Cheki M, Yahyapour R, Farhood B, et al. COX-2 in radiotherapy: A potential target for radioprotection and radiosensitization. Curr Mol Pharmacol 2018; 11: 173-83.
Najafi M, Motevaseli E, Shirazi A, et al. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: Clinical implications. Int J Radiat Biol 2018; 94: 335-56.
Yahyapour R, Amini P, Rezapoor S, et al. Targeting of inflammation for radiation protection and mitigation. Curr Mol Pharmacol 2018; 11: 203-10.
Yahyapour R, Shabeeb D, Cheki M, et al. Radiation protection and mitigation by natural antioxidants and flavonoids; implications to radiotherapy and radiation disasters. Curr Mol Pharmacol 2018; 11(4): 285-304.
Yang C, Tang H, Wang L, et al. Dimethyl sulfoxide prevents radiation-induced oral mucositis through facilitating DNA double-strand break repair in epithelial stem cell . Int J Radiat Oncol Biol Phys. 2018. S0360-3016 (18): 33467-9.
Oronsky B, Goyal S, Kim MM, et al. A review of clinical radioprotection and chemoprotection for oral mucositis. Transl Oncol 2018; 11: 771-8.
Tchanque-Fossuo CN, Donneys A, Deshpande SS, et al. Radioprotection with amifostine enhances bone strength and regeneration and bony union in a rat model of mandibular distraction Osteogen. Ann Plast Surg 2018; 80: 176-80.
Monson LA, Nelson NS, Donneys A, et al. amifostine treatment mitigates the damaging effects of radiation on distraction osteogenesis in the murine mandible. Ann Plast Surg 2016; 77: 164-8.
Gajowik A, Dobrzynska MM. Lycopene - antioxidant with radioprotective and anticancer properties. A review. Rocz Panstw Zakl Hig 2014; 65: 263-71.
de Freitas Cuba L, Salum FG, Cherubini K, de Figueiredo MA. Antioxidant agents: A future alternative approach in the prevention and treatment of radiation-induced oral mucositis? Altern Ther Health Med 2015; 21: 36-41.
Amber KT, Shiman MI, Badiavas EV. The use of antioxidants in radiotherapy-induced skin toxicity. Integr Cancer Ther 2014; 13: 38-45.
Farhood B, Goradel NH, Mortezaee K, et al. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization. Clin Transl Oncol
[ 10.1007/s12094-018-1934-0]
Yahyapour R, Amini P, Rezapour S, et al. Radiation-induced inflammation and autoimmune diseases. Mil Med Res 2018; 5: 9.
Yahyapour R, Motevaseli E, Rezaeyan A, et al. Mechanisms of radiation bystander and non-targeted effects: Implications to radiation carcinogenesis and radiotherapy. Curr Radiopharm 2018; 11: 34-45.
Saini D, Shelke S, Mani Vannan A, et al. Transcription profile of DNA damage response genes at G(0) lymphocytes exposed to gamma radiation. Mol Cell Biochem 2012; 364: 271-81.
Cooper KL, King BS, Sandoval MM, Liu KJ, Hudson LG. Reduction of arsenite-enhanced ultraviolet radiation-induced DNA damage by supplemental zinc. Toxicol Appl Pharmacol 2013; 269: 81-8.
Folkes LK, O’Neill P. Modification of DNA damage mechanisms by nitric oxide during ionizing radiation. Free Radic Biol Med 2013; 58: 14-25.
Huerta S, Gao X, Dineen S, Kapur P, Saha D, Meyer J. Role of p53, Bax, p21, and DNA-PKcs in radiation sensitivity of HCT-116 cells and xenografts. Surgery 2013; 154: 143-51.
Werner LR, Huang S, Francis DM, et al. Small molecule inhibition of MDM2-p53 interaction augments radiation response in human tumors. Mol Cancer Ther 2015; 14: 1994-2003.
Maebayashi K, Mitsuhashi N, Takahashi T, Sakurai H, Niibe H. p53 mutation decreased radiosensitivity in rat yolk sac tumor cell lines. Int J Radiat Oncol Biol Phys 1999; 44: 677-82.
Sugihara T, Murano H, Nakamura M, Ichinohe K, Tanaka K. p53-Mediated gene activation in mice at high doses of chronic low-dose-rate gamma radiation. Radiat Res 2011; 175: 328-35.
Csuka O, Remenar E, Koronczay K, Doleschall Z, Nemeth G. Predictive value of p53, Bcl2 and bax in the radiotherapy of head and neck cancer. Pathol Oncol Res 1997; 3: 204-10.
Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol 2015; 25: 11-7.
Gaipl US, Multhoff G, Scheithauer H, et al. Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy. Immunotherapy 2014; 6: 597-610.
Barnett GC, West CML, Dunning AM, et al. Normal tissue reactions to radiotherapy: Towards tailoring treatment dose by genotype. Nat Rev Cancer 2009; 9: 134-42.
Peters LJ. Radiation therapy tolerance limits. For one or for all? Janeway Lecture. Cancer 1996; 77: 2379-85.
Wang Q, Ye T, Chen HL, Zhang XG, Zhang LZ. Correlation between intensity modulated radiotherapy and bone marrow suppression in breast cancer. Eur Rev Med Pharmacol Sci 2016; 20: 75-81.
Hui B, Zhang Y, Shi F, et al. Association between bone marrow dosimetric parameters and acute hematologic toxicity in cervical cancer patients undergoing concurrent chemoradiotherapy: Comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy. Int J Gynecol Cancer 2014; 24: 1648-52.
Su H, Ganapathy S, Li X, Yuan ZM, Ha CS. p53-Based strategy for protection of bone marrow from Y-90 Ibritumomab Tiuxetan. Int J Radiat Oncol Biol Phys 2015; 92: 1116-22.
Yokota T, Onoe T, Ogawa H, et al. Distinctive mucositis and feeding-tube dependency in cetuximab plus radiotherapy for head and neck cancer. Jpn J Clin Oncol 2015; 45: 183-8.
Musha A, Shimada H, Shirai K, et al. Prediction of acute radiation mucositis using an oral mucosal dose surface model in carbon ion radiotherapy for head and neck Tumors. PLoS One 2015; 10: e0141734.
Hernandez-Moreno A, Vidal-Casariego A, Calleja-Fernandez A, et al. Chronic enteritis in patients undergoing pelvic radiotherapy: Prevalence, risk factors and associated complications. Nutr Hosp 2015; 32: 2178-83.
Curtis MJ, Hays JB. Cooperative responses of DNA-damage-activated protein kinases ATR and ATM and DNA translesion polymerases to replication-blocking DNA damage in a stem-cell niche. DNA Repair (Amst) 2011; 10: 1272-81.
Iwamoto K, Hamada H, Eguchi Y, Okamoto M. Stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage. PLoS One 2014; 9: e101333.
Najafi M, Hashemi Goradel N, Farhood B, et al. Macrophage polarity in cancer: A review. J Cell Biochem 2019; 120(3): 2756-5.
Hekim N, Cetin Z, Nikitaki Z, Cort A, Saygili EI. Radiation triggering immune response and inflammation. Cancer Lett 2015; 368: 156-63.
Stoecklein VM, Osuka A, Ishikawa S, Lederer MR, Wanke-Jellinek L, Lederer JA. Radiation exposure induces inflammasome pathway activation in immune cells. J Immunol 2015; 194: 1178-89.
Singh VK, Pollard HB. Patents for Toll-like receptor ligands as radiation countermeasures for acute radiation syndrome. Expert Opin Ther Pat 2015; 25: 1085-92.
Hu Z, Xing Y, Qian Y, et al. Anti-radiation damage effect of polyethylenimine as a toll-like receptor 5 targeted agonist. J Radiat Res 2013; 54: 243-50.
Krivokrysenko VI, Toshkov IA, Gleiberman AS, et al. The toll-like receptor 5 agonist entolimod mitigates lethal acute radiation syndrome in non-human primates. PLoS One 2015; 10: e0135388.
Burdelya LG, Krivokrysenko VI, Tallant TC, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 2008; 320: 226-30.
Hellweg CE. The Nuclear Factor kappaB pathway: A link to the immune system in the radiation response. Cancer Lett 2015; 368: 275-89.
Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 2007; 13: 460-9.
Janot L, Sirard JC, Secher T, et al. Radioresistant cells expressing TLR5 control the respiratory epithelium’s innate immune responses to flagellin. Eur J Immunol 2009; 39: 1587-96.
Di Maggio FM, Minafra L, Forte GI, et al. Portrait of inflammatory response to ionizing radiation treatment. J Inflamm 2015; 12: 14.
Westbury CB, Yarnold JR. Radiation fibrosis current clinical and therapeutic perspectives. Clin Oncol (R Coll Radiol) 2012; 24: 657-72.
Westbury CB, Haviland J, Davies S, et al. Cytokine levels as biomarkers of radiation fibrosis in patients treated with breast radiotherapy. Radiat Oncol 2014; 9: 103.
Wernicke AG, Greenwood EA, Coplowitz S, et al. Tissue compliance meter is a more reproducible method of measuring radiation-induced fibrosis than late effects of normal tissue-subjective objective management analytical in patients treated with intracavitary brachytherapy accelerated partial breast irradiation: Results of a prospective trial. Breast J 2013; 19: 250-8.
Li L, Steinauer KK, Dirks AJ, Husbeck B, Gibbs I, Knox SJ. Radiation-induced cyclooxygenase 2 up-regulation is dependent on redox status in prostate cancer cells. Radiat Res 2003; 160: 617-21.
Ogura A, Oowada S, Kon Y, et al. Redox regulation in radiation-induced cytochrome <em>c</em> release from mitochondria of human lung carcinoma A549 cells. Cancer Lett 2009; 277: 64-71.
Edvardsen H, Landmark-Hoyvik H, Reinertsen KV, et al. SNP in TXNRD2 associated with radiation-induced fibrosis: A study of genetic variation in reactive oxygen species metabolism and signaling. Int J Radiat Oncol Biol Phys 2013; 86: 791-9.
Farhood B, Goradel NH, Mortezaee K, Khanlarkhani N, Najafi M, Sahebkar A. Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment. J Cell Physiol 2018.
Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334: 574-9.
Najafi M, Cheki M, Rezapoor S, et al. Metformin: Prevention of genomic instability and cancer: A review. Mutat Res 2018; 827: 1-8.
Yang Y, Li B, Liu C, et al. Hydrogen-rich saline protects immunocytes from radiation-induced apoptosis. Med Sci Monit 2012; 18: Br144-8.
Chuai Y, Qian L, Sun X, Cai J. Molecular hydrogen and radiation protection. Free Radic Res 2012; 46: 1061-7.
Gómez-García A, Martínez Torres G, Ortega-Pierres LE, Rodríguez-Ayala E, Álvarez-Aguilar C. Rosuvastatin and metformin decrease inflammation and oxidative stress in patients with hypertension and dyslipidemia. Rev Esp Cardiol 2007; 60: 1242-9.
Shin HS, Ko J, Kim DA, et al. Metformin ameliorates the phenotype transition of peritoneal mesothelial cells and peritoneal fibrosis via a modulation of oxidative stress. Sci Rep 2017; 7: 5690.
Chukwunonso Obi B, Chinwuba Okoye T, Okpashi VE, Nonye Igwe C, Olisah Alumanah E. Comparative study of the antioxidant effects of metformin, glibenclamide, and repaglinide in alloxan-induced diabetic rats. J Diab Res 2016; 2016: 1635361.
Esteghamati A, Eskandari D, Mirmiranpour HM, et al. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: A randomized clinical trial. Clin Nutr 2013; 32: 179-85.
Mirmiranpour H, Mousavizadeh M, Noshad S, et al. Comparative effects of pioglitazone and metformin on oxidative stress markers in newly diagnosed type 2 diabetes patients: A randomized clinical trial. J Diab Complicat 2013; 27: 501-7.
Alsharidah M, Algeffari M, Abdel-Moneim AH, Lutfi MF, Alshelowi H. Effect of combined gliclazide/metformin treatment on oxidative stress, lipid profile, and hepatorenal functions in type 2 diabetic patients. Saudi Pharm J 2018; 26: 1-6.
Diniz Vilela D, Gomes Peixoto L, Teixeira RR, et al. The role of metformin in controlling oxidative stress in muscle of diabetic rats.oxidative medicine and cellular longevity 2016. 2016: 6978625.
Kelly B, Tannahill GM, Murphy MP, O’Neill LA. Metformin inhibits the production of reactive oxygen species from NADH: Ubiquinone oxidoreductase to limit induction of Interleukin-1beta (IL-1beta) and boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-activated macrophages. J Biol Chem 2015; 290: 20348-59.
Buldak L, Labuzek K, Buldak RJ, et al. Metformin affects macrophages’ phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages. Pharmacol Rep 2014; 66: 418-29.
Yahyapour R, Amini P, Saffar H, et al. Metformin protects against radiation-induced heart injury and attenuates the up-regulation of dual oxidase genes following rat’s chest irradiation Int J Mol Cell Med 2018. 7: 0-0.
Azmoonfar R, Amini P, Saffar H, et al. Metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression. Adv Pharm Bull 2018; 8(4): 697.
Shinde A, Berhane H, Rhieu BH, et al. Intraoral mitochondrial-targeted GS-Nitroxide, JP4-039, radioprotects normal tissue in tumor-bearing radiosensitive fancd2(−/−) (C57BL/6) mice. Radiat Res 2016; 185: 134-50.
Zhang JZ, Liu Z, Liu J, Ren JX, Sun TS. Mitochondrial DNA induces inflammation and increases TLR9/NF-kappaB expression in lung tissue. Int J Mol Med 2014; 33: 817-24.
Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci USA 2015; 112: 1809-14.
Watanabe M, Yamamoto H, Eikawa S, et al. Study about the efficacy of metformin to immune function in cancer patients. Acta Med Okayama 2016; 70: 327-30.
Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA 2013; 110: 972-7.
Buldak L, Machnik G, Buldak RJ, Labuzek K, Boldys A, Okopien B. Exenatide and metformin express their anti-inflammatory effects on human monocytes/macrophages by the attenuation of MAPKs and NFkappaB signaling. Naunyn Schmiedebergs Arch Pharmacol 2016; 389: 1103-15.
Schuiveling M, Vazirpanah N, Radstake T, Zimmermann M, Broen JCA. Metformin, a new era for an old drug in the treatment of immune mediated disease? Curr Drug Targets 2018; 19: 945-59.
Kim J, Kwak HJ, Cha JY, et al. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via Activating Transcription Factor-3 (ATF-3) induction. J Biol Chem 2014; 289: 23246-55.
Algire C, Moiseeva O, Deschenes-Simard X, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila) 2012; 5: 536-43.
Del Barco S, Vazquez-Martin A, Cufí S, et al. Metformin: Multi-faceted protection against cancer. Oncotarget 2011; 2: 896-917.
Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 2001; 276: 42462-7.
Adamovich Y, Adler J, Meltser V, Reuven N, Shaul Y. AMPK couples p73 with p53 in cell fate decision. Cell Death Differ 2014; 21: 1451-9.
Sanli T, Steinberg GR, Singh G, Tsakiridis T. AMP-activated Protein Kinase (AMPK) beyond metabolism: A novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol Ther 2014; 15: 156-69.
Dogan Turacli I, Candar T, Yuksel EB, Kalay S, Oguz AK, Demirtas S. Potential effects of metformin in DNA BER system based on oxidative status in type 2 diabetes. Biochimie 2018; 154: 62-8.
Xu G, Wu H, Zhang J, et al. Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic Biol Med 2015; 87: 15-25.
Cheki M, Shirazi A, Mahmoudzadeh A, Bazzaz JT, Hosseinimehr SJ. The radioprotective effect of metformin against cytotoxicity and genotoxicity induced by ionizing radiation in cultured human blood lymphocytes. Mutat Res 2016; 809: 24-32.
Kolivand S, Motevaseli E, Cheki M, Mahmoudzadeh A, Shirazi A, Fait V. The anti-apoptotic mechanism of metformin against apoptosis induced by ioniz ing radiation in human peripheral blood mononuclear cells. Klin Onkol 2017; 372.
Bikas A, Van Nostrand D, Jensen K, et al. Metformin attenuates 131i-induced decrease in peripheral blood cells in patients with differentiated thyroid cancer. Thyroid 2016; 26: 280-6.
Mujica-Mota MA, Salehi P, Devic S, Daniel SJ. Safety and otoprotection of metformin in radiation-induced sensorineural hearing loss in the guinea pig. Otolaryngol Head Neck Surg 2014; 150: 859-65.
Mansour HH, El Kiki SM, Galal SM. Metformin and low dose radiation modulates cisplatin-induced oxidative injury in rat via PPAR-gamma and MAPK pathways. Arch Biochem Biophys 2017; 616: 13-9.
Cohen EP, Fish BL, Irving AA, Rajapurkar MM, Shah SV, Moulder JE. Radiation nephropathy is not mitigated by antagonists of oxidative stress. Radiat Res 2009; 172: 260-4.
Gauter-Fleckenstein B, Fleckenstein K, Owzar K, et al. Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage. Free Radic Biol Med 2010; 48: 1034-43.
Jiang J, Belikova NA, Hoye AT, et al. A mitochondria-targeted nitroxide/hemigramicidin S conjugate protects mouse embryonic cells against gamma irradiation. Int J Radiat Oncol Biol Phys 2008; 70: 816-25.
Mahmood J, Jelveh S, Calveley V, Zaidi A, Doctrow SR, Hill RP. Mitigation of lung injury after accidental exposure to radiation. Radiat Res 2011; 176: 770-80.
Miller RC, Murley JS, Grdina DJ. Metformin exhibits radiation countermeasures efficacy when used alone or in combination with sulfhydryl containing drugs. Radiat Res 2014; 181: 464-70.
Cohen EP, Fish BL, Moulder JE. Mitigation of radiation injuries via suppression of the renin-angiotensin system: Emphasis on radiation nephropathy. Curr Drug Targets 2010; 11: 1423-9.
Mahmood J, Jelveh S, Calveley V, Zaidi A, Doctrow SR, Hill RP. Mitigation of lung injury after accidental exposure to radiation. Radiat Res 2011; 176: 770-80.
Mahmood J, Jelveh S, Zaidi A, Doctrow SR, Hill RP. Mitigation of radiation-induced lung injury with EUK-207 and genistein: Effects in adolescent rats. Radiat Res 2013; 179: 125-34.
Wang J, Wang Y, Han J, et al. Metformin attenuates radiation-induced pulmonary fibrosis in a murine model. Radiat Res 2017; 188: 105-13.
Belyi D, Kovalenko A, Bazyka D, Bebeshko V. Non-cancer effects in acute radiation syndrome survivors in Ukraine. Health Phys 2010; 98: 876-84.
Kim JM, Yoo H, Kim JY, et al. Metformin alleviates radiation-induced skin fibrosis via the downregulation of FOXO3. Cell Physiol Biochem 2018; 48: 959-70.
Grdina DJ, Murley JS, Miller RC, et al. A survivin-associated adaptive response in radiation therapy. Cancer Res 2013; 73: 4418-28.
Schaue D. A century of radiation therapy and adaptive immunity. Front Immunol 2017; 8: 431.
Park B, Yee C, Lee KM. The effect of radiation on the immune response to cancers. Int J Mol Sci 2014; 15: 927-43.
Najafi M, Farhood B, Mortezaee K. Extracellular Matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem 2019; 120(3): 2782-90.
Najafi M, Farhood B, Mortezaee K. Contribution of regulatory T cells to cancer: A review. J Cell Physiol 2018. [Epub ahead of print].
Shiao SL, Coussens LM. The tumor-immune microenvironment and response to radiation therapy. J Mammary Gland Biol Neoplasia 2010; 15: 411-21.
Jiang W, Chan CK, Weissman IL, Kim BYS, Hahn SM. Immune priming of the tumor microenvironment by radiation. Trends Cancer 2016; 2: 638-45.
Burnette B, Weichselbaum RR. Radiation as an immune modulator. Semin Radiat Oncol 2013; 23: 273-80.
Zhang C, Yang X, Zhang Q, et al. STAT3 inhibitor NSC74859 radiosensitizes esophageal cancer via the downregulation of HIF-1alpha. Tumour Biol 2014; 35: 9793-9.
Hennessey D, Martin LM, Atzberger A, Lynch TH, Hollywood D, Marignol L. Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells. Urol Oncol 2013; 31: 1106-16.
Goncalves Ndo N, Rodrigues RV, Jardim-Perassi BV, et al. Molecular markers of angiogenesis and metastasis in lines of oral carcinoma after treatment with melatonin. Anticancer Agents Med Chem 2014; 14: 1302-11.
Bailey ST, Miron PL, Choi YJ, et al. NF-kappaB activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth. Mol Cancer Res 2014; 12: 408-20.
Chaturvedi NK, Rajule RN, Shukla A, et al. Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-kappaB and mTOR dual-targeting approach. Mol Cancer Ther 2013; 12: 2006-17.
Shalapour S, Font-Burgada J, Di Caro G, et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 2015; 521: 94-8.
Freeman BE, Meyer C, Slifka MK. Anti-inflammatory cytokines directly inhibit innate but not adaptive CD8+ T cell functions. J Virol 2014; 88: 7474-84.
Tu Y, Liu L, Zhao D, et al. Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2. Sci Rep 2015; 5: 13827.
Stapor P, Wang X, Goveia J, Moens S, Carmeliet P. Angiogenesis revisited-role and therapeutic potential of targeting endothelial metabolism. J Cell Sci 2014; 127: 4331-41.
Guyot M, Hilmi C, Ambrosetti D, et al. Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies. Oncotarget 2017; 8: 9174-88.
Rizos CV, Elisaf MS. Metformin and cancer. Eur J Pharmacol 2013; 705: 96-108.
Biswas S, Chida AS, Rahman I. Redox modifications of protein-thiols: Emerging roles in cell signaling. Biochem Pharmacol 2006; 71: 551-64.
Mogavero A, Maiorana MV, Zanutto S, et al. Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep 2017; 7: 15992.
Farhood B, Najafi M, Salehi E, et al. Disruption of the redox balance with either oxidative or anti‐oxidative overloading as a promising target for cancer therapy. J Cell Biochem 2018. [Epub ahead of print].
Mortezaee K, Goradel NH, Amini P, et al. NADPH oxidase as a target for modulation of radiation response; implications to carcinogenesis and radiotherapy. Curr Mol Pharmacol 2019; 12(1): 50-60.
Ashabi G, Khalaj L, Khodagholi F, Goudarzvand M, Sarkaki A. Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab Brain Dis 2015; 30: 747-54.
Evia-Viscarra ML, Rodea-Montero ER, Apolinar-Jimenez E, et al. The effects of metformin on inflammatory mediators in obese adolescents with insulin resistance: Controlled randomized clinical trial. J Pediatr Endocrinol Metab 2012; 25: 41-9.
Nna VU, Abu Bakar AB, Md Lazin M, Mohamed M. Antioxidant, anti-inflammatory and synergistic anti-hyperglycemic effects of Malaysian propolis and metformin in streptozotocin-induced diabetic rats. Food Chem Toxicol 2018; 120: 305-20.
Cervia D, Assi E, De Palma C, et al. Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin. Oncotarget 2016; 7: 24995-5009.
Qian W, Li J, Chen K, et al. Metformin suppresses tumor angiogenesis and enhances the chemosensitivity of gemcitabine in a genetically engineered mouse model of pancreatic cancer. Life Sci 2018; 208: 253-61.
Wang JC, Li GY, Li PP, et al. Suppression of hypoxia-induced excessive angiogenesis by metformin via elevating tumor blood perfusion. Oncotarget 2017; 8: 73892-904.
Candido S, Abrams SL, Steelman L, et al. Metformin influences drug sensitivity in pancreatic cancer cells. Adv Biol Regul 2018; 68: 13-30.
Martinez-Outschoorn U, Sotgia F, Lisanti MP. Tumor microenvironment and metabolic synergy in breast cancers: Critical importance of mitochondrial fuels and function. Semin Oncol 2014; 41: 195-216.
Avagliano A, Granato G, Ruocco MR, et al. Metabolic reprogramming of cancer associated fibroblasts: The slavery of stromal fibroblasts. BioMed Res Int 2018; 2018: 6075403.
Farhood B, Najafi M, Mortezaee K. Cancer‐associated fibroblasts: Secretions, interactions, and therapy. J Cell Biochem 2019; 120(3): 2791-800.
Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, et al. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: Visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 2011; 10: 4047-64.
Li Y, Wang M, Zhi P, You J, Gao J-Q. Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models. Oncotarget 2018; 9: 2158-74.
Andrzejewski S, Gravel SP, Pollak M, St-Pierre J. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab 2014; 2: 12.
Wheaton WW, Weinberg SE, Hamanaka RB, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 2014; 3: e02242.
Ohnishi S, Mizutani H, Kawanishi S. The enhancement of oxidative DNA damage by anti-diabetic metformin, buformin, and phenformin, via nitrogen-centered radicals. Free Radic Res 2016; 50: 929-37.
Song CW, Lee H, Dings RP, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep 2012; 2: 362.
Liu J, Hou M, Yuan T, et al. Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair. Oncol Rep 2012; 28: 1406-12.
Cheng G, Zielonka J, Ouari O, et al. Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Res 2016; 76: 3904-15.
Zhang Y, Storr SJ, Johnson K, et al. Involvement of metformin and AMPK in the radioresponse and prognosis of luminal versus basal-like breast cancer treated with radiotherapy. Oncotarget 2014; 5: 12936-49.
Kim EH, Kim MS, Furusawa Y, et al. Metformin enhances the radiosensitivity of human liver cancer cells to γ-rays and carbon ion beams. Oncotarget 2016; 7: 80568.
Fasih A, Elbaz HA, Huttemann M, Konski AA, Zielske SP. Radiosensitization of pancreatic cancer cells by metformin through the AMPK pathway. Radiat Res 2014; 182: 50-9.
Wang Z, Lai ST, Ma NY, et al. Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair. Cancer Lett 2015; 369: 192-201.
Jeong YK, Kim MS, Lee JY, Kim EH, Ha H. Metformin radiosensitizes p53-deficient colorectal cancer cells through induction of G2/M arrest and inhibition of DNA repair proteins. PLoS One 2015; 10: e0143596.
Muaddi H, Chowdhury S, Vellanki R, Zamiara P, Koritzinsky M. Contributions of AMPK and p53 dependent signaling to radiation response in the presence of metformin. Radiother Oncol 2013; 108: 446-50.
Maity A, Cerniglia G, Daurio N, et al. Targeting the PI3K/mTOR pathway reduces tumor hypoxia and decreases oxygen consumption. Int J Radiat Oncol Biol Phys 2013; 87: S170.
Song X, Feng L, Liang C, Gao M, Song G, Liu Z. Liposomes co-loaded with metformin and chlorin e6 modulate tumor hypoxia during enhanced photodynamic therapy. Nano Res 2017; 10: 1200-12.
Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res 2017; 5(1): 9-16.
Dal Pra A, Zannella V, Glicksman R, et al. Metformin and prostate cancer radiation therapy: Improved outcomes due to enhanced tumor oxygenation. international journal of radiation oncology• Biol Phys 2013. 87: S170
Zannella VE, Dal Pra A, Muaddi H, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res 2013; 19(24): 6741-50.
Ma SJ, Zheng YX, Zhou PC, Xiao YN, Tan HZ. Metformin use improves survival of diabetic liver cancer patients: Systematic review and meta-analysis. Oncotarget 2016; 7: 66202-11.
Xu H, Chen K, Jia X, et al. Metformin use is associated with better survival of breast cancer patients with diabetes: A meta-analysis. Oncologist 2015; 20: 1236-44.
Ma SJ, Zheng YX, Zhou PC, Xiao YN, Tan HZ. Metformin use improves survival of diabetic liver cancer patients: Systematic review and meta-analysis. Oncotarget 2016; 7: 66202-11.
Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009; 27: 3297-302.
Li M, Li X, Zhang H, Lu Y. Molecular mechanisms of metformin for diabetes and cancer treatment. Front Physiol 2018; 9: 1039.
Meng F, Song L, Wang W. Metformin improves overall survival of colorectal cancer patients with diabetes: A meta-analysis. J Diabetes Res 2017; 2017: 5063239.
Tang YL, Zhu LY, Li Y, et al. Metformin use is associated with reduced incidence and improved survival of endometrial cancer: A meta-analysis. BioMed Res Int 2017; 2017: 5905384.
Hu J, Chen JB, Cui Y, et al. Association of metformin intake with bladder cancer risk and oncologic outcomes in type 2 diabetes mellitus patients: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97: e11596.
Han K, Pintilie M, Lipscombe LL, Lega IC, Milosevic MF, Fyles AW. Association between metformin use and mortality after cervical cancer in older women with diabetes. Cancer Epidemiol Biomarkers Prev 2016; 25: 507-12.
Gash KJ, Chambers AC, Cotton DE, Williams AC, Thomas MG. Potentiating the effects of radiotherapy in rectal cancer: The role of aspirin, statins and metformin as adjuncts to therapy. Br J Cancer 2017; 117: 210-9.
Ferro A, Goyal S, Kim S, et al. Evaluation of diabetic patients with breast cancer treated with metformin during adjuvant radiotherapy. Int J Breast Cancer 2013; 2013: 659723.
Jang WI, Kim MS, Lim JS, et al. Survival advantage associated with metformin usage in hepatocellular carcinoma patients receiving radiotherapy: A propensity score matching analysis. Anticancer Res 2015; 35: 5047-54.
Skinner HD, Crane CH, Garrett CR, et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med 2013; 2: 99-107.
Park JW, Lee JH, Park YH, et al. Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients. World J Gastroenterol 2017; 23: 5196-205.
Du L, Wang M, Kang Y, et al. Prognostic role of metformin intake in diabetic patients with colorectal cancer: An updated qualitative evidence of cohort studies. Oncotarget 2017; 8: 26448-59.
Skinner HD, Crane CH, Garrett CR, et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med 2013; 2: 99-107.
Ki Y-J, Kim HJ, Kim MS, et al. Association between metformin use and survival in nonmetastatic rectal cancer treated with a curative resection: A nationwide population study. Cancer Res Treat Official J Korean Cancer Assoc 2017; 49: 29-36.
Oh BY, Park YA, Huh JW, et al. Metformin enhances the response to radiotherapy in diabetic patients with rectal cancer. J Cancer Res Clin Oncol 2016; 142: 1377-85.
Wink KC, Belderbos JS, Dieleman EM, et al. Improved progression free survival for patients with diabetes and locally advanced Non-Small Cell Lung Cancer (NSCLC) using metformin during concurrent chemoradiotherapy. Radiother Oncol 2016; 118: 453-9.

© 2022 Bentham Science Publishers | Privacy Policy