Abstract
The biguanide metformin, a widely used antidiabetic drug, has received great interest in oncology research in recent years after an epidemiological study showed a link between metformin treatment and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. Rotenone, a well-known strong mitochondrial complex I inhibitor, yet associated with toxic effects, has also shown anti-cancer activity. Thus, we compared metformin and phenformin, another biguanide previously on the market as antidiabetic, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. Therefore, we conducted in vivo rat studies with metformin and phenformin, based on an experimental design previously described for mechanistic investigations of the effects of rotenone, including blood and tissue analysis, histopathology and gene expression profiling. These investigations show that the mechanistic profile of phenformin appears similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displays only transient similarities after one day of treatment. A potential reason may be that metformin, but not rotenone or phenformin, self-limits its entry into mitochondria due to its molecular properties. Thus, our detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, but should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.
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Data availability statement
The gene expression data are available from the Gene Expression Omnibus (GEO) database (accession numbers GSE86353 and GSE122609), https://www.ncbi.nlm.nih.gov/geo/. Further datasets generated or analyzed during this study are included in the manuscript and its Supplementary material. Any other raw data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Abdo KM (1988) NTP Technical report on the toxicology and carcinogenesis studies of rotenone in F344/N Rats and B6C3F1 mice technical report series No 320. US Department of Health and Human Services, USA
Abdo KM, Eustis SL, Haseman J, Huff JE, Peters A, Persing R (1988) Toxicity and carcinogenicity of rotenone given in the feed to F344/N rats and B6C3F1 mice for up to two years. Drug Chem Toxicol 11(3):225–235. https://doi.org/10.3109/01480548809017879
Algire C, Moiseeva O, Deschenes-Simard X et al (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 5(4):536–543. https://doi.org/10.1158/1940-6207.CAPR-11-0536
Algire C, Ehrmann A, Christian S, et al (2015) Differential effects of metformin and phenformin versus other Complex I inhibitors in vitro and in vivo. In: AACR 106th Annual Meeting 2015 https://doi.org/10.1158/1538-7445.am2015-1126.Philadelphia (PA), April 18-22
Anisimov VN, Berstein LM, Egormin PA et al (2005a) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40(8–9):685–693. https://doi.org/10.1016/j.exger.2005.07.007
Anisimov VN, Egormin PA, Bershtein LM et al (2005b) Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med 139(6):721–723
Anisimov VN, Berstein LM, Popovich IG et al (2011) If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY) 3(2):148–157. https://doi.org/10.18632/aging.100273
Appleyard MV, Murray KE, Coates PJ et al (2012) Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer 106(6):1117–1122. https://doi.org/10.1038/bjc.2012.56
Araujo AA, Pereira A, Medeiros C et al (2017) Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS One 12(8):e0183506. https://doi.org/10.1371/journal.pone.0183506
Ashinuma H, Takiguchi Y, Kitazono S et al (2012) Antiproliferative action of metformin in human lung cancer cell lines. Oncol Rep 28(1):8–14. https://doi.org/10.3892/or.2012.1763
Batandier C, Guigas B, Detaille D et al (2006) The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr 38(1):33–42. https://doi.org/10.1007/s10863-006-9003-8
Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3(12):1301–1306. https://doi.org/10.1038/81834
Birsoy K, Possemato R, Lorbeer FK et al (2014) Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508(7494):108–112. https://doi.org/10.1038/nature13110
Bojkova B, Orendas P, Garajova M et al (2009) Metformin in chemically-induced mammary carcinogenesis in rats. Neoplasma 56(3):269–274
Bridges HR, Jones AJ, Pollak MN, Hirst J (2014) Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 462(3):475–487. https://doi.org/10.1042/BJ20140620
Brunmair B, Staniek K, Gras F et al (2004) Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53(4):1052–1059
Cameron AR, Logie L, Patel K et al (2018) Metformin selectively targets redox control of complex I energy transduction. Redox Biol 14:187–197. https://doi.org/10.1016/j.redox.2017.08.018
Caraci F, Chisari M, Frasca G et al (2003) Effects of phenformin on the proliferation of human tumor cell lines. Life Sci 74(5):643–650
Chae YK, Arya A, Malecek MK et al (2016) Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7(26):40767–40780. https://doi.org/10.18632/oncotarget.8194
Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ (2006) Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol Endocrinol Metab 291(1):E182–E189. https://doi.org/10.1152/ajpendo.00272.2005
Cunningham ML, Soliman MS, Badr MZ, Matthews HB (1995) Rotenone, an anticarcinogen, inhibits cellular proliferation but not peroxisome proliferation in mouse liver. Cancer Lett 95(1–2):93–97
Detaille D, Guigas B, Chauvin C et al (2005) Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 54(7):2179–2187
Dilman VM, Anisimov VN (1980) Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C3H/Sn mice. Gerontology 26(5):241–246
Dilman VM, Berstein LM, Zabezhinski MA, Alexandrov VA, Bobrov JF, Pliss GB (1978) Inhibition of DMBA-induced carcinogenesis by phenformin in the mammary gland of rats. Arch Geschwulstforsch 48(1):1–8
Drahota Z, Palenickova E, Endlicher R et al (2014) Biguanides inhibit complex I, II and IV of rat liver mitochondria and modify their functional properties. Physiol Res 63(1):1–11 (Academia Scientiarum Bohemoslovaca)
Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y (2008) Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol 233(2):203–210. https://doi.org/10.1016/j.taap.2008.08.013
El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275(1):223–228
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330(7503):1304–1305. https://doi.org/10.1136/bmj.38415.708634.F7
Fato R, Bergamini C, Bortolus M et al (2009) Differential effects of mitochondrial Complex I inhibitors on production of reactive oxygen species. Biochim Biophys Acta 1787(5):384–392. https://doi.org/10.1016/j.bbabio.2008.11.003
Feldmann B, Jehle PM, Mohan S et al (2000) Diabetic retinopathy is associated with decreased serum levels of free IGF-I and changes of IGF-binding proteins. Growth Horm IGF Res 10(1):53–59. https://doi.org/10.1054/ghir.2000.0140
Fogal V, Richardson AD, Karmali PP, Scheffler IE, Smith JW, Ruoslahti E (2010) Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol 30(6):1303–1318. https://doi.org/10.1128/MCB.01101-09
Geoghegan F, Chadderton N, Farrar GJ, Zisterer DM, Porter RK (2017) Direct effects of phenformin on metabolism/bioenergetics and viability of SH-SY5Y neuroblastoma cells. Oncol Lett 14(5):6298–6306. https://doi.org/10.3892/ol.2017.6929
Gunton JE, Delhanty PJ, Takahashi S, Baxter RC (2003) Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrino Metabol 88(3):1323–1332. https://doi.org/10.1210/jc.2002-021394
Hawley SA, Boudeau J, Reid JL et al (2003) Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2(4):28. https://doi.org/10.1186/1475-4924-2-28
Hawley SA, Ross FA, Chevtzoff C et al (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11(6):554–565. https://doi.org/10.1016/j.cmet.2010.04.001
He L, Wondisford FE (2015) Metformin action: concentrations matter. Cell Metab 21(2):159–162. https://doi.org/10.1016/j.cmet.2015.01.003
Heinz S, Freyberger A, Lawrenz B, Schladt L, Schmuck G, Ellinger-Ziegelbauer H (2017) Mechanistic investigations of the mitochondrial complex i inhibitor rotenone in the context of pharmacological and safety evaluation. Sci Rep 7:45465. https://doi.org/10.1038/srep45465
Herzig S, Long F, Jhala US et al (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413(6852):179–183. https://doi.org/10.1038/35093131
Hundal RS, Krssak M, Dufour S et al (2000) Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49(12):2063–2069
Hunter RW, Hughey CC, Lantier L et al (2018) Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat Med 24(9):1395–1406. https://doi.org/10.1038/s41591-018-0159-7
Isenberg JS, Kolaja KL, Ayoubi SA, Watkins JB 3rd, Klaunig JE (1997) Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone. Carcinogenesis 18(8):1511–1519
Ish-Shalom D, Christoffersen CT, Vorwerk P et al (1997) Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia 40(Suppl 2):25–31
Jackson AL, Sun W, Kilgore J et al (2017) Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer. Oncotarget 8(59):100113–100127. https://doi.org/10.18632/oncotarget.22012
Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K (2014) Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci USA 111(29):10574–10579. https://doi.org/10.1073/pnas.1409844111
Jeon SM (2016) Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48(7):e245. https://doi.org/10.1038/emm.2016.81
Jia Y, Ma Z, Liu X et al (2015) Metformin prevents DMH-induced colorectal cancer in diabetic rats by reversing the warburg effect. Cancer Med 4(11):1730–1741. https://doi.org/10.1002/cam4.521
Jin DH, Kim Y, Lee BB et al (2017) Metformin induces cell cycle arrest at the G1 phase through E2F8 suppression in lung cancer cells. Oncotarget 8(60):101509–101519. https://doi.org/10.18632/oncotarget.21552
Kasznicki J, Sliwinska A, Drzewoski J (2014) Metformin in cancer prevention and therapy. Ann Transl Med 2(6):57. https://doi.org/10.3978/j.issn.2305-5839.2014.06.01
Kheder S, Sisley K, Hadad S, Balasubramanian SP (2017) Effects of prolonged exposure to low dose metformin in thyroid cancer cell lines. J Cancer 8(6):1053–1061. https://doi.org/10.7150/jca.16584
Kheirandish M, Mahboobi H, Yazdanparast M, Kamal W, Kamal MA (2018) Anti-cancer effects of metformin: recent evidences for its role in prevention and treatment of cancer. Curr Drug Metab. https://doi.org/10.2174/1389200219666180416161846
Ko Y, Choi A, Lee M, Lee JA (2016) Metformin displays in vitro and in vivo antitumor effect against osteosarcoma. Korean J Pediatr 59(9):374–380. https://doi.org/10.3345/kjp.2016.59.9.374
Li N, Ragheb K, Lawler G et al (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278(10):8516–8525. https://doi.org/10.1074/jbc.M210432200
Losco P (1992) Normal Development, Growth, and Aging of the Spleen. In: Mohr U, Dungworth DL, Capen CC (eds) Pathobiology of the aging rat, vol 1. ILSI Press, Washington
Lu R, Yang J, Wei R et al (2018) Synergistic anti-tumor effects of liraglutide with metformin on pancreatic cancer cells. PLoS One 13(6):e0198938. https://doi.org/10.1371/journal.pone.0198938
Luengo A, Sullivan LB, Heiden MG (2014) Understanding the complex-I-ty of metformin action: limiting mitochondrial respiration to improve cancer therapy. BMC Biol 12:82. https://doi.org/10.1186/s12915-014-0082-4
MacKay HJ, Levine DA, Bae-Jump VL et al (2017) Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials. Oncotarget 8(48):84579–84594. https://doi.org/10.18632/oncotarget.19961
Madiraju AK, Erion DM, Rahimi Y et al (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510(7506):542–546. https://doi.org/10.1038/nature13270
Madiraju AK, Qiu Y, Perry RJ et al (2018) Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24(9):1384–1394. https://doi.org/10.1038/s41591-018-0125-4
Medina JM, Sanchez-Medina F, Mayor F (1971) Effect of phenformin on gluconeogenesis in perfused rat liver. Rev Esp Fisiol 27(3):253–256
Meng S, Cao J, He Q et al (2015) Metformin activates AMP-activated protein kinase by promoting formation of the alphabetagamma heterotrimeric complex. J Biol Chem 290(6):3793–3802. https://doi.org/10.1074/jbc.M114.604421
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494(7436):256–260. https://doi.org/10.1038/nature11808
Miskimins WK, Ahn HJ, Kim JY, Ryu S, Jung YS, Choi JY (2014) Synergistic anti-cancer effect of phenformin and oxamate. PLoS One 9(1):e85576. https://doi.org/10.1371/journal.pone.0085576
Mogavero A, Maiorana MV, Zanutto S et al (2017) Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep 7(1):15992. https://doi.org/10.1038/s41598-017-16149-z
Ogata K, Jomain-Baum M, Hanson RW (1974) Phenethylbiguanide and the inhibition of hepatic gluconeogenesis in the guinea pig. Biochem J 144(1):49–57
Orecchioni S, Reggiani F, Talarico G et al (2015) The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int J Cancer 136(6):E534–E544. https://doi.org/10.1002/ijc.29193
Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348(Pt 3):607–614
Pernicova I, Korbonits M (2014) Metformin–mode of action and clinical implications for diabetes and cancer. Nature Rev Endocrinol 10(3):143–156. https://doi.org/10.1038/nrendo.2013.256
Pollak M (2013) Potential applications for biguanides in oncology. J Clin Investig 123(9):3693–3700. https://doi.org/10.1172/JCI67232
Pollak M (2014) Overcoming drug development bottlenecks with repurposing: repurposing biguanides to target energy metabolism for cancer treatment. Nat Med 20(6):591–593. https://doi.org/10.1038/nm.3596
Rastegar M, Marjani HA, Yazdani Y, Shahbazi M, Golalipour M, Farazmandfar T (2018) Investigating effect of rapamycin and metformin on angiogenesis in hepatocellular carcinoma cell line. Adv Pharm Bull 8(1):63–68. https://doi.org/10.15171/apb.2018.008
Rauchova H, Vokurkova M, Drahota Z (2014) Inhibition of mitochondrial glycerol-3-phosphate dehydrogenase by alpha-tocopheryl succinate. Int J Biochem Cell Biol 53:409–413. https://doi.org/10.1016/j.biocel.2014.06.010
Saad A, Palm M, Widwell S, Reiland S (2000) Differential analysis of rat bone marrow by flow cytometry. Comp Haematol Int 10(2):97–101
Schäfer G (1983) Biguanides. A review of history, pharmacodynamics and therapy. Diabetes Metabol 9(2):148–163
Schockel L, Glasauer A, Basit F et al (2015) Targeting mitochondrial complex I using BAY 87-2243 reduces melanoma tumor growth. Cancer Metab 3:11. https://doi.org/10.1186/s40170-015-0138-0
Schulz M, Schmoldt A (2003) Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 58(7):447–474
Scotland S, Saland E, Skuli N et al (2013) Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia 27(11):2129–2138. https://doi.org/10.1038/leu.2013.107
Shackelford DB, Abt E, Gerken L et al (2013) LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23(2):143–158. https://doi.org/10.1016/j.ccr.2012.12.008
Shaw RJ, Lamia KA, Vasquez D et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310(5754):1642–1646. https://doi.org/10.1126/science.1120781
Shitara Y, Nakamichi N, Norioka M, Shima H, Kato Y, Horie T (2013) Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria. Toxicol Sci 132(1):32–42. https://doi.org/10.1093/toxsci/kfs330
Stephenne X, Foretz M, Taleux N et al (2011) Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 54(12):3101–3110. https://doi.org/10.1007/s00125-011-2311-5
Talpade DJ, Greene JG, Higgins DS Jr, Greenamyre JT (2000) In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. J Neurochem 75(6):2611–2621
Tanner CM, Kamel F, Ross GW et al (2011) Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect 119(6):866–872. https://doi.org/10.1289/ehp.1002839
Thakur S, Daley B, Gaskins K et al (2018) Metformin targets mitochondrial glycerophosphate dehydrogenase to control rate of oxidative phosphorylation and growth of thyroid cancer in vitro and in vivo. Clin Cancer Res. https://doi.org/10.1158/1078-0432.ccr-17-3167
Tutwiler GF, Fawthrop H (1983) Effect of the oral hypoglycemic agent pirogliride (MCN-3495) on glycogen levels of normal and diabetic rats. Biochem Int 7(1):55–62
Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y (2003) Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 63(4):844–848
Wang Y, Li G, Goode J et al (2012) Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485(7396):128–132. https://doi.org/10.1038/nature10988
Weinberg F, Hamanaka R, Wheaton WW et al (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 107(19):8788–8793. https://doi.org/10.1073/pnas.1003428107
Wheaton WW, Weinberg SE, Hamanaka RB et al (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 3:e02242. https://doi.org/10.7554/eLife.02242
Wiernsperger NF, Bailey CJ (1999) The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 58(Suppl 1):31–39
Williams RH, Palmer JP (1975) Farewell to phenformin for treating diabetes mellitus. Ann Intern Med 83(4):567–568
Xie W, Wang L, Sheng H et al (2017) Metformin induces growth inhibition and cell cycle arrest by upregulating MICRORNA34A in renal cancer cells. Med Sci Monit 23:29–37
Yoon JC, Puigserver P, Chen G et al (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413(6852):131–138. https://doi.org/10.1038/35093050
Yoshitani SI, Tanaka T, Kohno H, Takashima S (2001) Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone. Int J Oncol 19(5):929–939
Yousef M, Tsiani E (2017) Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies. Cancers (Basel). https://doi.org/10.3390/cancers9050045
Yuan L, Ziegler R, Hamann A (2002) Inhibition of phosphoenolpyruvate carboxykinase gene expression by metformin in cultured hepatocytes. Chin Med J (Engl) 115(12):1843–1848
Zhang L, He H, Balschi JA (2007) Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol 293(1):H457–H466. https://doi.org/10.1152/ajpheart.00002.2007
Zhang CS, Li M, Ma T et al (2016) Metformin activates AMPK through the Lysosomal Pathway. Cell Metab 24(4):521–522. https://doi.org/10.1016/j.cmet.2016.09.003
Zhao RX, Xu ZX (2014) Targeting the LKB1 tumor suppressor. Curr Drug Targets 15(1):32–52
Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig 108(8):1167–1174. https://doi.org/10.1172/JCI13505
Zi F, Zi H, Li Y, He J, Shi Q, Cai Z (2018) Metformin and cancer: an existing drug for cancer prevention and therapy. Oncol Lett 15(1):683–690. https://doi.org/10.3892/ol.2017.7412
Acknowledgements
The authors would like to thank Sabine Michel-Kaulmann, Kerstin Noklies, Michael Rosentreter and the teams of P. Buchmann, A. Freyberger, E. Hartmann, B. Lawrenz and L. Schladt for technical assistance. In addition, we acknowledge Björn Riefke, Markus Slopianka and Beatrice Broszat for valuable advices regarding FACS-analysis. Finally, we thank Dr. Thomas Steger-Hartmann for continuous support.
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Heinz, S., Freyberger, A., Lawrenz, B. et al. Energy metabolism modulation by biguanides in comparison with rotenone in rat liver and heart. Arch Toxicol 93, 2603–2615 (2019). https://doi.org/10.1007/s00204-019-02519-1
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DOI: https://doi.org/10.1007/s00204-019-02519-1