Metformin preferentially enhances the radio-sensitivity of cancer stem-like cells with highly mitochondrial respiration ability in HMPOS

Eramo, 2008, Identification and expansion of the tumorigenic lung cancer stem cell population, Cell Death Differ., 15, 504, 10.1038/sj.cdd.4402283 Visvader, 2008, Cancer stem cells in solid tumours: accumulating evidence and unresolved questions, Nat. Rev. Cancer, 8, 755, 10.1038/nrc2499 Baumann, 2010, CD44: a cancer stem cell-related biomarker with predictive potential for radiotherapy, Clin. Cancer Res., 16, 5091, 10.1158/1078-0432.CCR-10-2244 Cao, 2011, Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines, BMC Gastroenterol., 11, 71, 10.1186/1471-230X-11-71 Tirino, 2011, Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo, FASEB J., 25, 2022, 10.1096/fj.10-179036 Soeda, 2008, Epidermal growth factor plays a crucial role in mitogenic regulation of human brain tumor stem cells, J. Biol. Chem., 283, 10958, 10.1074/jbc.M704205200 Murase, 2009, Side population cells have the characteristics of cancer stem-like cells/cancer-initiating cells in bone sarcomas, Br. J. Cancer, 101, 1425, 10.1038/sj.bjc.6605330 Deguchi, 2019, Analysis of radiosensitivity of cancer stem-like cells derived from canine cancer cell lines, Vet. Comp. Oncol., 17, 119, 10.1111/vco.12452 Samsuri, 2017, Metformin and improved treatment outcomes in radiation therapy - a review, Cancer Treat. Rev., 55, 150, 10.1016/j.ctrv.2017.03.005 Song, 2012, Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells, Sci. Rep., 2, 362, 10.1038/srep00362 Owen, 2000, Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain, Biochem. J., 348, 607, 10.1042/bj3480607 Rena, 2017, The mechanisms of action of metformin, Diabetologia, 60, 1577, 10.1007/s00125-017-4342-z Rocha, 2011, Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth, Clin. Cancer Res., 17, 3993, 10.1158/1078-0432.CCR-10-2243 Lonardo, 2013, Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells, PLoS ONE, 8, e76518, 10.1371/journal.pone.0076518 Song, 2013, Metformin potentiates the effects of radiation on cancer cells and cancer stem cells by activating Ampk, Int. J. Radiat. Oncol. Biol. Phys., 87, S653, 10.1016/j.ijrobp.2013.06.1731 Cheng, 2016, Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells, Cancer Res., 76, 3904, 10.1158/0008-5472.CAN-15-2534 Mohammed, 2013, Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling, Transl. Oncol., 6, 649, 10.1593/tlo.13556 Fasih, 2014, Radiosensitization of pancreatic cancer cells by metformin through the AMPK pathway, Radiat. Res., 182, 50, 10.1667/RR13568.1 Biswas, 2006, Redox modifications of protein-thiols: emerging roles in cell signaling, Biochem. Pharmacol., 71, 551, 10.1016/j.bcp.2005.10.044 Hou, 2018, Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation, J. Cell. Mol. Med., 22, 1316 Birsoy, 2014, Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides, Nature, 508, 108, 10.1038/nature13110 Kalyanaraman, 2017, Modified metformin as a more potent anticancer drug: mitochondrial inhibition, redox signaling, antiproliferative effects and future EPR studies, Cell Biochem. Biophys., 75, 311, 10.1007/s12013-017-0796-3 Zhou, 2011, Metabolic alterations in highly tumorigenic glioblastoma cells: preference for hypoxia and high dependency on glycolysis, J. Biol. Chem., 286, 32843, 10.1074/jbc.M111.260935 Sun, 2017, Metabolic analysis of radioresistant medulloblastoma stem-like clones and potential therapeutic targets, PLoS ONE, 12, e0176162, 10.1371/journal.pone.0176162 Folmes, 2011, Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming, Cell Metab., 14, 264, 10.1016/j.cmet.2011.06.011 Solaini, 2011, Oxidative phosphorylation in cancer cells, Biochim. Biophys. Acta, 1807, 534, 10.1016/j.bbabio.2010.09.003 Yamamori, 2012, Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint, Free Radic. Biol. Med., 53, 260, 10.1016/j.freeradbiomed.2012.04.033 Gao, 2016, Cancer stem cells in small cell lung cancer cell line H446: higher dependency on oxidative phosphorylation and mitochondrial substrate-level phosphorylation than non-stem cancer cells, PLoS ONE, 11, e0154576, 10.1371/journal.pone.0154576 Azzam, 2012, Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury, Cancer Lett., 327, 48, 10.1016/j.canlet.2011.12.012 Pawlik, 2004, Role of cell cycle in mediating sensitivity to radiotherapy, Int. J. Radiat. Oncol. Biol. Phys., 59, 928, 10.1016/j.ijrobp.2004.03.005 Goetze, 2013, Glycolysis-related gene induction and ATP reduction during fractionated irradiation. Markers for radiation responsiveness of human tumor xenografts, Strahlenther. Onkol., 189, 782, 10.1007/s00066-013-0371-9 Lynam-Lennon, 2014, Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma, PLoS ONE, 9, e100738, 10.1371/journal.pone.0100738 Bao, 2007, Chromatin remodeling in DNA double-strand break repair, Curr. Opin. Genet. Dev., 17, 126, 10.1016/j.gde.2007.02.010 Johnston, 2017, Pharmacokinetics and oral bioavailability of metformin hydrochloride in healthy mixed-breed dogs, Am. J. Vet. Res., 78, 1193, 10.2460/ajvr.78.10.1193 Barroga, 1999, Establishment and characterization of the growth and pulmonary metastasis of a highly lung metastasizing cell line from canine osteosarcoma in nude mice, J. Vet. Med. Sci., 61, 361, 10.1292/jvms.61.361 Yamamoto, 2018, Genotoxic responses of mitochondrial oxygen consumption rate and mitochondrial semiquinone radicals in tumor cells, Appl. Magn. Reson., 49, 837, 10.1007/s00723-018-1007-0 Cottet-Rousselle, 2011, Cytometric assessment of mitochondria using fluorescent probes, Cytometry A, 79, 405, 10.1002/cyto.a.21061