A+ A A-

Download article


Kulikov V.A., Belyaeva L.E.
Cancer cell metabolism as a therapeutic target
Vitebsk State Order of Peoples’ Friendship Medical University, Vitebsk, Republic of Belarus

Vestnik VGMU. 2016;15(6):7-20.

Aerobic glycolysis, which was for the first time described 90 years ago by the biochemist Otto Warburg, represents the brightest metabolic feature of cancer cells. Other important features of the metabolism change in cancer cells are active use of glutamine and synthesis of the fatty acids. Despite the fact that these metabolic distinctions between normal and cancer cells are not absolute, they can serve as a biochemical basis for the development of new antineoplastic medicinal agents. The inhibition of glycolysis, intervention in glutamine exchange and fatty acids synthesis process are three possible approaches in antineoplastic therapy. Mitochondrial dysfunction, oncogenes activation, antioncogenes suppression, the conditions of tumour cells microenvironment exert an expressed influence on cancer cells  metabolism and cause heterogeneity of metabolic profiles among various types of tumours.  The importance of determining specific metabolic changes for each malignant tumour is obvious in order to have the possibility to effectively influence its growth. Besides, the combination of traditional chemotherapeutic drugs and metabolic modulators can enchance the efficacy of antineoplastic therapy.
Key words: metabolism, cancer, Warburg effect, glutaminolysis.

1. Hanahan D. Hallmarks of cancer: the next generation. Cell. 2011 Mar;144(5):646-74. doi:
2. Kulikov VA, Belyaeva LE. About Bioenergy tumor cells. Vestn VGMU. 2015;14(6):5-14. (In Russ.)
3. Kulikov VA, Belyaeva LE. Metabolic reprogramming of cancer cells. Vestn VGMU. 2013;12(2):5-18. (In Russ.)
4. Smolková K, Plecitá-Hlavatá L, Bellance N, Benard G, Rossignol R, Ježek P. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol. 2011 Jul;43(7):950-68. doi:
5. Jose C, Rossignol R. Rationale for mitochondria-targeting strategies in cancer bioenergetic therapies. Int J Biochem Cell Biol. 2013 Jan;45(1):123-9. doi:
6. Chen Z, Zhang H, Lu W, Huang P. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta. 2009 May;1787(5):553-60. doi:
7. Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell. 2013 Aug;24(2):213-28. doi:
8. Maher JC, Krishan A, Lampidis TJ. Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol. 2004 Feb;53(2):116-22. doi:
9. Zhao Y, Butler EB, Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013 Mar;4:e532. doi:
10. Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun. 2004 Nov;324(1):269-75. doi:
11. Pedersen PL. Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr. 2007 Jun;39(3):211-22. doi:
12. Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL. A translational study «case report» on the small molecule «energy blocker» 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr. 2012 Feb;44(1):163-70. doi:
13. Guo L, Shestov AA, Worth AJ, Nath K, Nelson DS, Leeper DB, et al. Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine. J Biol Chem. 2016 Jan;291(1):42-57. doi:
14. Hammoudi N, Ahmed KB, Garcia-Prieto C, Huang P. Metabolic alterations in cancer cells and therapeutic implications. Chin J Cancer. 2011 Aug;30(8):508-25. doi:
15. Milane L, Duan Z, Amiji M. Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer. PLoS One. 2011;6(9):e24075. doi:
16. Farabegoli F, Vettraino M, Manerba M, Fiume L, Roberti M, Di Stefano G. Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signalling pathways. Eur J Pharm Sci. 2012 Nov;47(4):729-38. doi:
17. Colen CB, Shen Y, Ghoddoussi F, Yu P, Francis TB, Koch BJ, et al. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia. 2011 Jul;13(7):620-32.
18. Mathupala SP, Ko YH, Pedersen PL. The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1225-30. doi:
19. Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase a novel therapeutic target in oncology. Front Oncol. 2013 Mar;3:38. doi:
20. Shen H, Decollogne S, Dilda PJ, Hau E, Chung SA, Luk PP, et al. Dual-targeting of aberrant glucose metabolism in glioblastoma. J Exp Clin Cancer Res. 2015 Feb;34:14. doi:
21. Szablewski L. Expression of glucose transporters in cancers. Biochim Biophys Acta. 2013 Apr;1835(2):164-9. doi:
22. Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, et al. Small molecule inhibition of 6-phosphofructo-2- kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther. 2008 Jan;7(1):110-20. doi:
23. Clem BF, O'Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther. 2013 Aug;12(8):1461-70. doi:
24. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012 Nov;22(5):585-600. doi:
25. Shannon E, Chen J. Targeting glucosae metabolism in patients with cancer. Cancer. 2014 Mar;120(6):774-80. doi:
26. Zhao Y, Liu H, Riker AI, Fodstad O, Ledoux SP, Wilson GL, et al. Emerging Metabolic Targets in Cancer Therapy. Front Biosci (Landmark Ed). 2011 Jan;16:1844-60.
27. Weijer R, Broekgaarden M, Krekorian M, Alles LK, van Wijk AC, Mackaaij C, et al. Inhibition of hypoxia inducible factor 1 and topoisomerase with acriflavine sensitizes perihilar cholangiocarcinomas to photodynamic therapy. Oncotarget. 2016 Jan;7(3):3341-56. doi:
28. Schmid P, Pinder SE, Wheatley D, Macaskill J, Zammit C, Hu J, et al. Phase II randomized preoperative window-of-opportunity study of the pi3k inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2016 Jun;34(17):1987-94. doi:
29. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Mortarini R, Viviani1 S, et al. Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases. Clin Cancer Res. 2014;20(22):5641-51.
30. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, еt al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008 Jul;7(7):1851-63. doi:
31. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009 Oct;69(19):7507-11. doi:
32. Bost F, Decoux-Poullot AG, Tanti JF, Clavel S. Energy disruptors: rising stars in anticancer therapy? Oncogenesis. 2016 Jan;5:e188.
33. Kee HJ, Cheong JH. Tumor bioenergetics: an emеrging avenue for cancer metabolism targeted therapy. BMB Rep. 2014 Mar;47(3):158-66.
34. Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E. Energy metabolism in tumor cells. FEBS J. 2007 Mar;274(6):1393-418. doi:
35. Pelicano H, Xu RH, Du M, Feng L, Sasaki R, Carew JS, et al. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J Cell Biol. 2006 Dec;175(6):913-23. doi:
36. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 2011 Mar;25(5):460-70. doi:
37. Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008 Dec;118(12):3930-42.
38. Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, et al. Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol. 2011 Jul;43(7):1045-51. doi:
39. Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, et al. The autophagic tumor stroma model of cancer or «battery-operated tumor growth»: A simple solution to the autophagy paradox. Cell Cycle. 2010 Nov;9(21):4297-306. doi:
40. Deng YT, Huang HC, Lin JK. Rotenone induces apoptosis in MCF-7 human breast cancer cell-mediated ROS through JNK and p38 signaling. Mol Carcinog. 2010 Feb;49(2):141-51. doi:
41. Dong LF, Low P, Dyason JC, Wang XF, Prochazka L, Witting PK, et al. Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene. 2008 Jul;27(31):4324-35. doi:
42. Xiao D, Powolny AA, Singh SV. Benzyl isothiocyanate targets mitochondrial respiratory chain to trigger reactive oxygen species-dependent apoptosis in human breast cancer cells. J Biol Chem. 2008 Oct;283(44):30151-63. doi:
43. Li YC, Fung KP, Kwok TT, Lee CY, Suen YK, Kong SK. Mitochondria-targeting drug oligomycin blocked P-glycoprotein activity and triggered apoptosis in doxorubicin-resistant HepG2 cell. Chemotherapy. 2004 Jun;50(2):55-62. doi:
44. Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci. 2011 Jan;1215:161-9. doi:
45. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010 Sep;18(3):207-19. doi:
46. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, and clinical opportunities. J Clin Invest. 2013 Sep;123(9):3678-84. doi:
47. Thornburg JM, Nelson KK, Clem BF, Lane AN, Arumugam S, Simmons A, et al. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res. 2008;10(5):R84. doi:
48. Vincent EE, Sergushichev A, Griss T, Gingras MC, Samborska B, Ntimbane T. Mitochondrial phosphoenolpyruvate carboxykinase regmulates metabolic adaptation and enables glucose-independent tumor growth. Mol Cell. 2015 Oct;60(2):195-207. doi:
49. Méndez-Lucas A, Hyroššová P, Novellasdemunt L, Viñals F, Perales JC. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor Cell adaptation to nutrient availability. J Biol Chem. 2014 Aug;289(32):22090-102. doi:

Information about authors:
Kulikov V.A. – Candidate of Medical Sciences, associate professor, head of the Chair of General and Clinical Biochemistry with the course of the Faculty for Advanced Training & Retraining, Vitebsk State Order of Peoples’ Friendship Medical University;
Belyaeva L.E. – Candidate of Medical Sciences, associate professor, head of the Chair of Pathologic Physiology, Vitebsk State Order of Peoples’ Friendship Medical University.

Correspondence address: Republic of Belarus, 210023, Vitebsk, 27 Frunze ave., Vitebsk State Order of Peoples’ Friendship Medical University, Chair of General and Clinical Biochemistry with the course of the Faculty for Advanced Training & Retraining. E-mail: Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра. –Kulikov Vyacheslav A.

Поиск по сайту