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Targeting cancer energy metabolism: a potential systemic cure for cancer

  • Soo-Youl KimEmail author
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Abstract

Long-term investigation and extensive efforts using sequencing and -omics analysis identified thousands of mutations in a single tumor. However, we cannot succeed at curing cancer by targeting mutations as the cause of cancer. Therefore, as an alternate therapeutic approach from classical oncology study, stimulation of the inherent ability of the immune system to attack tumor cells was welcome as a new principle in cancer therapy. However, it cannot be a permanent solution for the question of “which is the common factor that can distinguish cancer from normal?” Targeting the cancer energy metabolism may be a cancer-specific therapy for all kinds of cancer because normal cells do not rely on cancer energy metabolism under normal conditions. Here, trends of cancer metabolism as well as a new theory of cancer energy metabolism in the therapeutic approach is summarized.

Keywords

Cancer Energy metabolism Anticancer Oxidative phosphorylation Cancer specific therapy 

Notes

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017R1A2B2003428).

Compliance with ethical standards

Conflict of interest

The author declared no conflict of interest.

References

  1. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24(41):6314–6322.  https://doi.org/10.1038/sj.onc.1208773 Google Scholar
  2. Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, Wang T, Chen WW, Clish CB, Sabatini DM (2014) Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508(7494):108–112.  https://doi.org/10.1038/nature13110 Google Scholar
  3. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S (1991) Oncogenes and signal transduction. Cell 64(2):281–302Google Scholar
  4. Chajes V, Cambot M, Moreau K, Lenoir GM, Joulin V (2006) Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res 66(10):5287–5294.  https://doi.org/10.1158/0008-5472.CAN-05-1489 Google Scholar
  5. Chen MC, Lee NH, Ho TJ, Hsu HH, Kuo CH, Kuo WW, Lin YM, Tsai FJ, Tsai CH, Huang CY (2014) Resistance to irinotecan (CPT-11) activates epidermal growth factor receptor/nuclear factor kappa B and increases cellular metastasis and autophagy in LoVo colon cancer cells. Cancer Lett 349(1):51–60.  https://doi.org/10.1016/j.canlet.2014.03.023 Google Scholar
  6. Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, Wa Cheng K, Hall H, Zhang D, Lu Y, Ravoori M, Kundra V, Ajani J, Lee JS, Ki Hong W, Mills GB (2011) Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther 10(12):2350–2362.  https://doi.org/10.1158/1535-7163.MCT-11-0497 Google Scholar
  7. Choi EJ, Jung BJ, Lee SH, Yoo HS, Shin EA, Ko HJ, Chang S, Kim SY, Jeon SM (2017) A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer. Oncogene 36(37):5285–5295.  https://doi.org/10.1038/onc.2017.153 Google Scholar
  8. Clementi E, Brown GC, Foxwell N, Moncada S (1999) On the mechanism by which vascular endothelial cells regulate their oxygen consumption. Proc Natl Acad Sci U S A 96(4):1559–1562Google Scholar
  9. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35.  https://doi.org/10.1016/j.cell.2012.03.003 Google Scholar
  10. Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA, Luengo A, Bauer MR, Jha AK, O’Brien JP, Pierce KA, Gui DY, Sullivan LB, Wasylenko TM, Subbaraj L, Chin CR, Stephanopolous G, Mott BT, Jacks T, Clish CB, Vander Heiden MG (2016) Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab 23(3):517–528.  https://doi.org/10.1016/j.cmet.2016.01.007 Google Scholar
  11. DeBerardinis RJ, Chandel NS (2016) Fundamentals of cancer metabolism. Sci Adv 2(5):e1600200.  https://doi.org/10.1126/sciadv.1600200 Google Scholar
  12. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104(49):19345–19350.  https://doi.org/10.1073/pnas.0709747104 Google Scholar
  13. Deep G, Agarwal R (2013) Targeting tumor microenvironment with silibinin: promise and potential for a translational cancer chemopreventive strategy. Curr Cancer Drug Targets 13(5):486–499Google Scholar
  14. 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):223–228Google Scholar
  15. Elwood JC, Lin YC, Cristofalo VJ, Weinhouse S, Morris HP (1963) Glucose utilization in homogenates of the morris hepatoma 5123 and related tumors. Cancer Res 23:906–913Google Scholar
  16. Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, Yang C, Do QN, Doucette S, Burguete D, Li H, Huet G, Yuan Q, Wigal T, Butt Y, Ni M, Torrealba J, Oliver D, Lenkinski RE, Malloy CR, Wachsmann JW, Young JD, Kernstine K, DeBerardinis RJ (2017) Lactate metabolism in human lung tumors. Cell 171(2):358–371.  https://doi.org/10.1016/j.cell.2017.09.019 Google Scholar
  17. Finley LW, Zhang J, Ye J, Ward PS, Thompson CB (2013) SnapShot: cancer metabolism pathways. Cell Metab 17(3):466.  https://doi.org/10.1016/j.cmet.2013.02.016 Google Scholar
  18. Flavin R, Peluso S, Nguyen PL, Loda M (2010) Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol 6(4):551–562.  https://doi.org/10.2217/fon.10.11 Google Scholar
  19. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT (2017) The PI3K pathway in human disease. Cell 170(4):605–635.  https://doi.org/10.1016/j.cell.2017.07.029 Google Scholar
  20. Fujiwara S, Kawano Y, Yuki H, Okuno Y, Nosaka K, Mitsuya H, Hata H (2013) PDK1 inhibition is a novel therapeutic target in multiple myeloma. Br J Cancer 108(1):170–178.  https://doi.org/10.1038/bjc.2012.527 Google Scholar
  21. Gao J, Chang MT, Johnsen HC, Gao SP, Sylvester BE, Sumer SO, Zhang H, Solit DB, Taylor BS, Schultz N, Sander C (2017) 3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets. Genome Med 9(1):4.  https://doi.org/10.1186/s13073-016-0393-x Google Scholar
  22. Glunde K, Bhujwalla ZM, Ronen SM (2011) Choline metabolism in malignant transformation. Nat Rev Cancer 11(12):835–848.  https://doi.org/10.1038/nrc3162 Google Scholar
  23. Guo L, Shestov AA, Worth AJ, Nath K, Nelson DS, Leeper DB, Glickson JD, Blair IA (2016) Inhibition of mitochondrial complex II by the anticancer agent lonidamine. J Biol Chem 291(1):42–57.  https://doi.org/10.1074/jbc.M115.697516 Google Scholar
  24. Guppy M, Leedman P, Zu X, Russell V (2002) Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J 364(Pt 1):309–315Google Scholar
  25. Hamanaka RB, Chandel NS (2012) Targeting glucose metabolism for cancer therapy. J Exp Med 209(2):211–215.  https://doi.org/10.1084/jem.20120162 Google Scholar
  26. Hensley CT, Wasti AT, DeBerardinis RJ (2013) Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest 123(9):3678–3684.  https://doi.org/10.1172/JCI69600 Google Scholar
  27. Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, Jiang L, Ko B, Skelton R, Loudat L, Wodzak M, Klimko C, McMillan E, Butt Y, Ni M, Oliver D, Torrealba J, Malloy CR, Kernstine K, Lenkinski RE, DeBerardinis RJ (2016) Metabolic heterogeneity in human lung tumors. Cell 164(4):681–694.  https://doi.org/10.1016/j.cell.2015.12.034 Google Scholar
  28. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, Shan C, Dai Q, Zhang L, Xie J, Gu TL, Jin P, Aleckovic M, LeRoy G, Kang Y, Sudderth JA, DeBerardinis RJ, Luan CH, Chen GZ, Muller S, Shin DM, Owonikoko TK, Lonial S, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Ye K, Boggon TJ, Kang S, He C, Chen J (2012) Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22(5):585–600.  https://doi.org/10.1016/j.ccr.2012.09.020 Google Scholar
  29. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13(10):714–726.  https://doi.org/10.1038/nrc3599 Google Scholar
  30. Jeon JH, Kim DK, Shin Y, Kim HY, Song B, Lee EY, Kim JK, You HJ, Cheong H, Shin DH, Kim ST, Cheong JH, Kim SY, Jang H (2016) Migration and invasion of drug-resistant lung adenocarcinoma cells are dependent on mitochondrial activity. Exp Mol Med 48(12):e277.  https://doi.org/10.1038/emm.2016.129 Google Scholar
  31. Johnson EA, Marks RS, Mandrekar SJ, Hillman SL, Hauge MD, Bauman MD, Wos EJ, Moore DF, Kugler JW, Windschitl HE, Graham DL, Bernath AM Jr, Fitch TR, Soori GS, Jett JR, Adjei AA, Perez EA (2008) Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51). Lung Cancer 60(2):200–207.  https://doi.org/10.1016/j.lungcan.2007.10.003 Google Scholar
  32. Kallinowski F, Schlenger KH, Runkel S, Kloes M, Stohrer M, Okunieff P, Vaupel P (1989) Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts. Cancer Res 49(14):3759–3764Google Scholar
  33. Kang JH, Lee SH, Hong D, Lee JS, Ahn HS, Ahn JH, Seong TW, Lee CH, Jang H, Hong KM, Lee C, Lee JH, Kim SY (2016a) Aldehyde dehydrogenase is used by cancer cells for energy metabolism. Exp Mol Med 48(11):e272.  https://doi.org/10.1038/emm.2016.103 Google Scholar
  34. Kang JH, Lee SH, Lee JS, Nam B, Seong TW, Son J, Jang H, Hong KM, Lee C, Kim SY (2016b) Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion. Oncotarget 7(31):49397–49410.  https://doi.org/10.18632/oncotarget.10354 Google Scholar
  35. Kim SY (2015a) Cancer metabolism: strategic diversion from targeting cancer drivers to targeting cancer suppliers. Biomol Ther (Seoul) 23(2):99–109.  https://doi.org/10.4062/biomolther.2015.013 Google Scholar
  36. Kim SY (2015b) Cancer metabolism: targeting cancer universality. Arch Pharm Res 38(3):299–301.  https://doi.org/10.1007/s12272-015-0551-5 Google Scholar
  37. Kim SY (2018a) Cancer energy metabolism: shutting power off cancer factory. Biomol Ther (Seoul) 26(1):39–44.  https://doi.org/10.4062/biomolther.2017.184 Google Scholar
  38. Kim SY (2018b) Cancer metabolism: a hope for curing cancer. Biomol Ther (Seoul) 26(1):1–3.  https://doi.org/10.4062/biomolther.2017.300 Google Scholar
  39. Kim EH, Lee JH, Oh Y, Koh I, Shim JK, Park J, Choi J, Yun M, Jeon JY, Huh YM, Chang JH, Kim SH, Kim KS, Cheong JH, Kim P, Kang SG (2017) Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin. Neuro Oncol 19(2):197–207.  https://doi.org/10.1093/neuonc/now174 Google Scholar
  40. LeBleu VS, O’Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, Asara JM, Kalluri R (2014) PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16 (10):992–1003, 1001–1015.  https://doi.org/10.1038/ncb3039
  41. Lee S, Lee JS, Seo J, Lee SH, Kang JH, Song J, Kim SY (2018) Targeting mitochondrial oxidative phosphorylation abrogated irinotecan resistance in NSCLC. Sci Rep 8(1):15707.  https://doi.org/10.1038/s41598-018-33667-6 Google Scholar
  42. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lubbert M, Hanel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Dohner K, Sauer M, Ganser A, Amadori S, Mandelli F, Dohner H, Ehninger G, Schlenk RF, Platzbecker U, Gruppo Italiano Malattie Ematologiche dA, German-Austrian Acute Myeloid Leukemia Study G, Study Alliance L (2013) Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369(2):111–121.  https://doi.org/10.1056/nejmoa1300874 Google Scholar
  43. Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP (2017a) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14(1):11–31.  https://doi.org/10.1038/nrclinonc.2016.60 Google Scholar
  44. Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP (2017b) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14(2):113.  https://doi.org/10.1038/nrclinonc.2017.1 Google Scholar
  45. Min HY, Lee HY (2018) Oncogene-driven metabolic alterations in cancer. Biomol Ther (Seoul) 26(1):45–56.  https://doi.org/10.4062/biomolther.2017.211 Google Scholar
  46. Morais-Santos F, Granja S, Miranda-Goncalves V, Moreira AH, Queiros S, Vilaca JL, Schmitt FC, Longatto-Filho A, Paredes J, Baltazar F, Pinheiro C (2015) Targeting lactate transport suppresses in vivo breast tumour growth. Oncotarget 6(22):19177–19189.  https://doi.org/10.18632/oncotarget.3910 Google Scholar
  47. Moreno-Sanchez R, Marin-Hernandez A, Saavedra E, Pardo JP, Ralph SJ, Rodriguez-Enriquez S (2014) Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. Int J Biochem Cell Biol 50:10–23.  https://doi.org/10.1016/j.biocel.2014.01.025 Google Scholar
  48. Nixon GL, Moss DM, Shone AE, Lalloo DG, Fisher N, O’Neill PM, Ward SA, Biagini GA (2013) Antimalarial pharmacology and therapeutics of atovaquone. J Antimicrob Chemother 68(5):977–985.  https://doi.org/10.1093/jac/dks504 Google Scholar
  49. Paquette M, El-Houjeiri L, Pause A (2018) mTOR pathways in cancer and autophagy. Cancers (Basel).  https://doi.org/10.3390/cancers10010018 Google Scholar
  50. Park J, Shim JK, Kang JH, Choi J, Chang JH, Kim SY, Kang SG (2018) Regulation of bioenergetics through dual inhibition of aldehyde dehydrogenase and mitochondrial complex I suppresses glioblastoma tumorspheres. Neuro Oncol 20(7):954–965.  https://doi.org/10.1093/neuonc/nox243 Google Scholar
  51. Pasto A, Bellio C, Pilotto G, Ciminale V, Silic-Benussi M, Guzzo G, Rasola A, Frasson C, Nardo G, Zulato E, Nicoletto MO, Manicone M, Indraccolo S, Amadori A (2014) Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation. Oncotarget 5(12):4305–4319.  https://doi.org/10.18632/oncotarget.2010 Google Scholar
  52. Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23(1):27–47.  https://doi.org/10.1016/j.cmet.2015.12.006 Google Scholar
  53. Pearce SF, Rebelo-Guiomar P, D’Souza AR, Powell CA, Van Haute L, Minczuk M (2017) Regulation of mammalian mitochondrial gene expression: recent advances. Trends Biochem Sci 42(8):625–639.  https://doi.org/10.1016/j.tibs.2017.02.003 Google Scholar
  54. Rani R, Kumar V (2016) Recent update on human lactate dehydrogenase enzyme 5 (hLDH5) inhibitors: a promising approach for cancer chemotherapy. J Med Chem 59(2):487–496.  https://doi.org/10.1021/acs.jmedchem.5b00168 Google Scholar
  55. Reznik E, Miller ML, Senbabaoglu Y, Riaz N, Sarungbam J, Tickoo SK, Al-Ahmadie HA, Lee W, Seshan VE, Hakimi AA, Sander C (2016) Mitochondrial DNA copy number variation across human cancers. Elife.  https://doi.org/10.7554/elife.10769 Google Scholar
  56. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK (2013) An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340(6132):626–630.  https://doi.org/10.1126/science.1236062 Google Scholar
  57. Schlaepfer IR, Rider L, Rodrigues LU, Gijon MA, Pac CT, Romero L, Cimic A, Sirintrapun SJ, Glode LM, Eckel RH, Cramer SD (2014) Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol Cancer Ther 13(10):2361–2371.  https://doi.org/10.1158/1535-7163.MCT-14-0183 Google Scholar
  58. Shriver LP, Manchester M (2011) Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci Rep 1:79.  https://doi.org/10.1038/srep00079 Google Scholar
  59. Smolkova K, Bellance N, Scandurra F, Genot E, Gnaiger E, Plecita-Hlavata L, Jezek P, Rossignol R (2010) Mitochondrial bioenergetic adaptations of breast cancer cells to aglycemia and hypoxia. J Bioenerg Biomembr 42(1):55–67.  https://doi.org/10.1007/s10863-009-9267-x Google Scholar
  60. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118(12):3930–3942.  https://doi.org/10.1172/JCI36843 Google Scholar
  61. Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458(7239):719–724.  https://doi.org/10.1038/nature07943 Google Scholar
  62. Tsuchida N, Ryder T, Ohtsubo E (1982) Nucleotide sequence of the oncogene encoding the p21 transforming protein of Kirsten murine sarcoma virus. Science 217(4563):937–939Google Scholar
  63. Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, Harlow EE, Xian J, Cantley LC (2010) Identification of small molecule inhibitors of pyruvate kinase M2. Biochem Pharmacol 79(8):1118–1124.  https://doi.org/10.1016/j.bcp.2009.12.003 Google Scholar
  64. Visentin M, Zhao R, Goldman ID (2012) The antifolates. Hematol Oncol Clin North Am 26(3):629–648.  https://doi.org/10.1016/j.hoc.2012.02.002 Google Scholar
  65. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339(6127):1546–1558.  https://doi.org/10.1126/science.1235122 Google Scholar
  66. Wagner BA, Venkataraman S, Buettner GR (2011) The rate of oxygen utilization by cells. Free Radic Biol Med 51(3):700–712.  https://doi.org/10.1016/j.freeradbiomed.2011.05.024 Google Scholar
  67. Warburg O (1956) On respiratory impairment in cancer cells. Science 124(3215):269–270Google Scholar
  68. Weinhouse S (1956) On respiratory impairment in cancer cells. Science 124(3215):267–269Google Scholar
  69. Wilson PM, Danenberg PV, Johnston PG, Lenz HJ, Ladner RD (2014) Standing the test of time: targeting thymidylate biosynthesis in cancer therapy. Nat Rev Clin Oncol 11(5):282–298.  https://doi.org/10.1038/nrclinonc.2014.51 Google Scholar
  70. Xiang Y, Stine ZE, Xia J, Lu Y, O’Connor RS, Altman BJ, Hsieh AL, Gouw AM, Thomas AG, Gao P, Sun L, Song L, Yan B, Slusher BS, Zhuo J, Ooi LL, Lee CG, Mancuso A, McCallion AS, Le A, Milone MC, Rayport S, Felsher DW, Dang CV (2015) Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J Clin Invest 125(6):2293–2306.  https://doi.org/10.1172/JCI75836 Google Scholar
  71. Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, Xie J, Tao M, Mao Y (2015) Metformin a with diabetes: a meta-analysis. Oncologist 20(11):1236–1244.  https://doi.org/10.1634/theoncologist.2015-0096 Google Scholar
  72. Yu M (2011) Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci 89(3–4):65–71.  https://doi.org/10.1016/j.lfs.2011.05.010 Google Scholar
  73. Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B (2013) Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A 110(45):18226–18231.  https://doi.org/10.1073/pnas.1317577110 Google Scholar
  74. Zu XL, Guppy M (2004) Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun 313(3):459–465Google Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Tumor Microenvironment Research Branch, Division of Basic Science, Research InstituteNational Cancer CenterGoyangRepublic of Korea

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