Anti-apoptotický mechanizmus metforminu proti apoptóze indukované ionizujícím zářením v mononukleárních buňkách lidské periferní krve
Authors:
S. Kolivand 1; E. Motevaseli 2,3; M. Cheki 4; A. Mahmoudzadeh 5; A. Shirazi 6; V. Fait 7
Authors‘ workplace:
Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences and Health Services
Tehran, Iran
1; Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences and Health Services
Tehran, Iran
2; Food Microbio logy Research Center, Tehran University of Medical Sciences and Health Services, Tehran, Iran
3; Department of Radiologic Technology, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
4; Department of Biosciences and Biotechnology, Malek Ashtar University of Technology, Tehran, Iran
5; Department of Medical Physics and Biomedical Engineering, Faculty of Medicine, Tehran University of Medical Sciences and Health Services, Tehran, Iran
6; Department of Surgical Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
7
Published in:
Klin Onkol 2017; 30(5): 372-379
Category:
Original Articles
doi:
https://doi.org/10.14735/amko2017372
Overview
Východiska:
V předchozím článku jsme ukázali, že metformin (MET) může snížit apoptózu indukovanou ionizační radiací (ionizing radiation – IR) v mononukleárních buňkách lidské periferní krve. Anti-apoptotický mechanizmus MET vůči IR však zůstává nejasný. Tato studie se pokouší ověřit mechanizmus působení MET v omezování rentgenem indukovanou apoptózu v mononukleárních buňkách lidské periferní krve.
Materiál a metody:
Mononukleární buňky byly 2 hod ošetřovány MET a ozářovány 6 Gy rentgenovými paprsky. Úrovně genové exprese BAX, CASP3 a BCL2 byly stanoveny 24 hod po ozáření za použití kvantitativní polymerázové řetězové reakce (qualitative polymerase chain reaction – qPCR) v reálném čase. Kromě toho byly hladiny proteinů BAX, CASP3 a BCL2 analyzovány pomocí metody Western blott.
Výsledky:
Radiační expozice zvýšila expresi genů BAX a CASP3 a snížila expresi genu BCL2 u mononukleárních buněk. Naopak, zvýšení exprese genu BCL2 spolu se snížením exprese genu BAX a CASP3 bylo pozorováno u MET a ozářených mononukleárních buněk. Bylo zjištěno, že záření zvýšilo poměr BAX/BCL2, zatímco MET snížil tento poměr. Také léčba s MET bez ozáření nezměnila expresi genů BAX, CASP3 a BCL2. Na druhou stranu snížená hladina proteinu BCL2 a zvýšená hladina proteinů BAX a CASP3 v 2 Gy ozářených mononukleárních buňkách, zatímco ovlivnění pomocí MET výrazně zvrátila tuto tendenci.
Závěr:
Výsledek naznačuje, že MET může chránit mononukleární buňky před apoptózou indukovanou IR prostřednictvím indukce buněčné anti-apoptotické signalizace.
Klíčová slova:
ionizující záření – metformin – apoptóza – geny – proteiny – krevní buňky
Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.
Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.
Obdrženo:
2. 8. 2017
Přijato:
7. 9. 2017
Sources
1. Cheki M, Mihandoost E, Shirazi A et al. Prophylactic role of some plants and phytochemicals against radio-genotoxicity in human lymphocytes. J Cancer Res Ther 2016; 12 (4): 1234–1242. doi: 10.4103/0973-1482.172131.
2. Cheki M, Shahbazi Gahrouei D, Moslehi M. Determination of organ absorbed doses in patients following bone scan with using of MIRD method. Iran South Med J 2013; 16 (5): 296–303.
3. Shahbazi-Gahrouei D, Cheki M, Moslehi M. Estimation of organ absorbed doses in patients from 99mTc-diphosphonate using the data of MIRDose software. J Med Signals Sens 2012; 2 (4): 231–234.
4. Viollet B, Guigas B, Sanz Garcia N et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122 (6): 253–270. doi: 10.1042/CS20110386.
5. Halicka HD, Zhao H, Li J et al. Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling. Aging (Albany NY) 2011; 3 (10): 1028–1038. doi: 10.18632/aging.100397.
6. Hou X, Song J, Li XN et al. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun 2010; 396 (2): 199–205. doi: 10.1016/j.bbrc.2010.04. 017.
7. Piwkowska A, Rogacka D, Jankowski M et al. Metformin induces suppression of NAD (P) H oxidase activity in podocytes. Biochem Biophys Res Commun 2010; 393 (2): 268–273. doi: 10.1016/j.bbrc.2010.01.119.
8. Brunmair B, Staniek K, Gras F et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic action? Diabetes 2004; 53 (4): 1052–1059.
9. Drose S, Hanley PJ, Brandt U. Ambivalent effects of diazoxide on mitochondrial ROS production at respiratory chain complexes I and III. Biochim Biophys Acta 2009; 1790 (6): 558–565. doi: 10.1016/j.bbagen.2009.01.011.
10. Lee SY, Lee SH, Yang EJ et al. Metformin Ameliorates Inflammatory Bowel Disease by Suppression of the STAT3 Signaling Pathway and Regulation of the between Th17/Treg Balance. PLoS One 2015; 10 (9): 1358–1358. doi: 10.1371/journal.pone.0135858.
11. Liu Y, Yang F, Ma W et al. Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytes in vitro via mTOR-signaling pathway. Pharm Biol 2016; 54 (7): 1173–1178. doi: 10.3109/13880209.2015.1057652.
12. Yeh CH, Chen TP, Wang YC et al. AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress. Mediators Inflamm 2010. doi: 10.1155/2010/130636.
13. Chang J, Jung HH, Yang JY et al. Protective role of antidiabetic drug metformin against gentamicin induced apoptosis in auditory cell line. Hear Res 2011; 282 (1–2): 92–96.
14. Koritzinsky M. Metformin: A novel biological modifier of tumor response to radiation therapy. Int J Radiat Oncol Biol Phys 2015; 93 (2): 454–464. doi: 10.1016/j.ijrobp.2015.06.003.
15. Cheki M, Shirazi A, Mahmoudzadeh A et al. The radioprotective effect of metformin against cytotoxicity and genotoxicity induced by ionizing radiation in cultured human blood lymphocytes. Mutat Res 2016; 809: 24–32. doi: 10.1016/j.mrgentox.2016.09.001.
16. Yuan JS, Reed A, Chen F et al. Statistical analysis of real-time PCR data. BMC Bioinformatics 2006; 7: 81–85. doi: 10.1186/1471-2105-7-85.
17. Kulkarni S, Ghosh SP, Hauer-Jensen M et al. Hematological targets of radiation damage. Curr Drug Targets 2010; 11 (11): 1375–1385.
18. Razzaghdoust A, Mozdarani H, Mofid B et al. Reduction in radiation-induced lymphocytopenia by famotidine in patients undergoing radiotherapy for prostate cancer. Prostate 2014; 74 (1): 41–47. doi: 10.1002/pros.22725.
19. De Giorgi U, Mego M, Scarpi E et al. Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer. Clin Breast Cancer 2012; 12 (4): 264–269. doi: 10.1016/j.clbc.2012.04.004.
20. Balmanoukian A, Ye X, Herman J et al. The association between treatment-related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas. Cancer Invest 2012; 30 (8): 571–576. doi: 10.3109/07357907.2012.700987.
21. Grossman SA, Ye X, Lesser G et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011; 17 (16): 5473–5480. doi: 10.1158/1078-0432.CCR-11-0774.
22. Lissoni P, Meregalli S, Bonetto E et al. Radiotherapy-induced lymphocytopenia: Changes in total lymphocyte count and in lymphocyte subpopulations under pelvic irradiation in gynecologic neoplasms. J Biol Regul Homeost Agents 2005; 19 (3–4): 153–158.
23. Xu P, Cai X, Zhang W et al. Flavonoids of Rosa roxburghii Tratt exhibit radioprotection and anti-apoptosis properties via the Bcl-2 (Ca (2+)) /Caspase-3/PARP-1 pathway. Apoptosis 2016; 21 (10): 1125–1143. doi: 10.1007/s10495-016-1270-1.
24. Shen Y, Luo Q, Xu H et al. Mitochondria-dependent apoptosis of activated T lymphocytes induced by astin C, a plant cyclopeptide, for preventing murine experimental colitis. Biochem Pharmacol 2011; 82 (3): 260–268. doi: 10.1016/j.bcp.2011.04.013.
25. Xia L, Luo QL, Lin HD et al. The effect of different treatment time of millimeter wave on chondrocyte apoptosiss, caspase-3, caspase-8, and MMP-13 express-ion in rabbit surgically induced model of knee osteoarthritis. Rheumatol Int 2012; 32 (9): 2847–2856. doi: 10.1007/s00296-011-2080-y.
26. Mohan S, Abdelwahab SI, Kamalidehghan B et al. Involvement of NF-κB and BCL2/BAX signaling pathways in the apoptosis of MCF7 cells induced by a xanthone compound Pyranocycloartobiloxanthone A. Phytomedicine 2012; 19 (11): 1007–1015. doi: 10.1016/j.phymed.2012.05.012.
27. Kluck RM, Bossy-Wetzel E, Green DR et al. The release of cytochrome C from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997; 275 (5303): 1132–1136.
28. Lindsten T, Zong WX, Thompson CB. Defining the role of the Bcl-2 family of proteins in the nervous system. Neuroscientist 2005; 11 (1): 10–15. doi: 10.1177/10738 58404269267.
29. Bivik CA, Larsson PK, Kagedal KM et al. UVA/B-Induced apoptosis in human melanocytes involves translocation of cathepsins and Bcl-2 family members. J Invest Dermatol 2006; 126 (5): 1119–1127. doi: 10.1038/sj.jid.5700124.
30. Green DR. At the gates of death. Cancer Cell 2006; 9 (5): 328–330. doi: 10.1016/j.ccr.2006.05.004.
31. Ullah I, Ullah N, Naseer MI et al. Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. BMC Neuroscience 2012; 13: 11. doi: 10.1186/1471-2202-13-11.
32. Chen D, Xia D, Pan Z et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis 2016; 7 (10): e2441. doi: 10.1038/cddis.2016.334.
33. Zhou C, Sun R, Zhuang S et al. Metformin prevents cerebellar granule neurons against glutamate-induced neurotoxicity. Brain Res Bull 2016; 121: 241–245. doi: 10.1016/j.brainresbull.2016.02.009.
34. de la Rosa LC, Vrenken TE, Buist-Homan M et al. Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis. Pharm Res Perspect 2015; 3 (2): e00125. doi: 10.1002/prp2.125.
35. Asensio-Lopez MC, Lax A, Pascual-Figal DA et al. Metformin protects against doxorubicin-induced cardiotoxicity: involvement of the adiponectin cardiac system. Free Radic Biol Med 2011; 51 (10): 1861–1871. doi: 10.1016/j.freeradbiomed.2011.08.015.
36. Ota K, Nakamura J, Li W et al. Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells. Biochem Biophys Res Commun 2007; 357 (1): 270–275. doi: 10.1016/j.bbrc.2007.03.140.
37. Guigas B, Detaille D, Chauvin C et al. Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study. Biochem J 2004; 382 (Pt 3): 877–884. doi: 10.1042/BJ20040885.
38. El-Mir MY, Detaille D, R-Villanueva G et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 2008; 34 (1): 77–87. doi: 10.1007/s12031-007-9002-1.
39. Morales AI, Detaille D, Prieto M et al. Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int 2010; 77 (10): 861–869. doi: 10.1038/ki.2010.11.
40. Park SJ, Ahn G, Lee NH et al. Phloroglucinol (PG) purified from Ecklonia cava attenuates radiation-induced apoptosis in blood lymphocytes and splenocytes. Food Chem Toxicol 2011; 49 (9): 2236–2242. doi: 10.1016/j.fct.2011.06.021.
41. Park E, Lee NH, Joo HG et al. Modulation of apoptosis of eckol against ionizing radiation in mice. Biochem Biophys Res Commun 2008; 372 (4): 792–797. doi: 10.1016/j.bbrc.2008.05.140.
42. Chen L, Liu Y, Dong L et al. Edaravone protects human peripheral blood lymphocytes from γ-irradiation-induced apoptosis and DNA damage. Cell Stress Chaperones 2015; 20 (2): 289–295. doi: 10.1007/s12192-014-0542-3.
43. Begum N, Prasad NR. Apigenin, a dietary antioxidant, modulates gamma radiation-induced oxidative damages in human peripheral blood lymphocytes. Biomed Prev Nut 2012; 2 (1): 16–24. doi: 10.1016/j.bionut.2011.11. 003.
44. Ghosh D, Dey SK, Saha C. Antagonistic effects of black tea against gamma radiation-induced oxidative damage to normal lymphocytes in comparison with cancerous K562 cells. Radiat Environ Biophys 2014; 53 (4): 695–704. doi: 10.1007/s00411-014-0551-8.
45. Wang XY, Ma ZC, Wang YG et al. Tetramethylpyrazine protects lymphocytes from radiation-induced apoptosis through nuclear factor-κB. Chin J Nat Med 2014; 12 (10): 730–737. doi: 10.1016/S1875-5364 (14) 60112-6.
46. Villunger A, Michalak EM, Coultas L et al. p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003; 302 (5647): 1036–1038. doi: 10.1126/science.1090072.
47. Bonnefont-Rousselot D, Raji B, Walrand S et al. An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. Metabolism 2003; 52 (5): 586–589. doi: 10.1053/meta.2003.50093.
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