Mitochondrial Processes in Targeted Cancer Therapy

Czech version

Authors: Krejčíř Radovan; Valík Dalibor; Vojtěšek Bořivoj
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2018; 31(Supplementum 2): 14-20
Category: Review
doi: https://doi.org/10.14735/amko20182S14

Overview

Background:

During tumor initiation and progress, cellular functions adapt to the new needs of the transformed cells and mitochondrial processes are also affected. Mitochondria are less extensively used for supplying cells with energy; rather, cancer cells utilize glycolysis to a much greater extent, even under aerobic conditions. Mitochondria produce metabolites required for cellular growth and proliferation. Mutations and alterations in gene expression of citrate cycle enzymes can directly contribute to transformation through the production of oncometabolites. The apoptotic pathway in which mitochondria play a critical role is disrupted in cancer cells, resulting in cells that do not respond to programmed cell death signaling. These differences between mitochondrial processes in healthy and diseased cells suggest they could be used in mitochondria-targeted therapies. To date, many potential molecular targets have been identified, including enzymes, signaling molecules, and membrane transporters. Even though this field has been studied for years, the first drugs, venetoclax and enasidenib, were only approved in the last two years and are the result of two different research approaches. Venetoclax targets the apoptotic pathway and enasidenib targets metabolic processes. The discovery of these two compounds demonstrates that it is possible to develop mitochondria-targeted cancer treatments.

Purpose:

The purpose of this article is to provide an overview of research in the field of mitochondria-targeting therapies for cancer. The main areas of research and the main approaches for treatment development are summarized. Cellular components studied as potential targets for therapy and compounds that are considered exploitable are described, as well as already approved drugs.

Key words:

neoplasms – molecular targeted therapy – mitochondria – antineoplastic agents – research

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Accepted: 3. 8. 2018

Sources

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144 (5): 646–674. doi: 10.1016/j.cell.2011.02.013.

2. Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 2010; 11 (9): 621–632. doi: 10.1038/nrm2 952.

3. Czabotar PE, Lessene G, Strasser A et al. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15 (1): 49–63. doi: 10.1038/nrm3722.

4. Ashkenazi A, Fairbrother WJ, Leverson JD et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 2017; 16 (4): 273–284. doi: 10.1038/nrd.2016.253.

5. Deeks ED. Venetoclax: first global approval. Drugs 2016; 76 (9): 979–987.

6. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol 1927; 8 (6): 519–530.

7. Hirschey MD, DeBerardinis RJ, Diehl AM et al. Dysregulated metabolism contributes to oncogenesis. Semin Cancer Biol 2015; 35 (Suppl): S129–S150. doi: 10.1016/j.semcancer.2015.10.002.

8. Kaňková K, Hrstka R. Nádory jako metabolická onemocnění a diabetes jako riziko nádorů? Klin Onkol 2012; 25 (Suppl 2): 26–31. doi: 10.14735/amko20122 S26.

9. Pedersen PL, Mathupala S, Rempel A et al. Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta 2002; 1555 (1–3): 14–20.

10. Patra KC, Wang Q, Bhaskar PT 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; 24 (2): 213–228. doi: 10.1016/j.ccr.2013.06.014.

11. Pelicano H, Martin DS, Xu RH et al. Glycolysis inhibition for anticancer treatment. Oncogene 2006; 25 (34): 4633–4646. doi: 10.1038/sj.onc.1209597.

12. Chen Z, Zhang H, Lu W et al. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta 2009; 1787 (5): 553–560. doi: 10.1016/j.bbabio.2009.03.003.

13. Yamamoto T, Seino Y, Fukumoto H et al. Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun 1990; 170 (1): 223–230.

14. Thorens B, Mueckler M. Glucose transporters in the 21^st century. Am J Physiol Endocrinol Metab 2010; 298 (2): E141–E145. doi: 10.1152/ajpendo.00712.2009.

15. Szablewski L. Expression of glucose transporters in cancers. Biochim Biophys Acta 2013; 1835 (2): 164–169. doi: 10.1016/j.bbcan.2012.12.004.

16. Zhang D, Li J, Wang F et al. 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett 2014; 355 (2): 176–183. doi: 10.1016/j.canlet.2014.09.003.

17. El Mjiyad N, Caro-Maldonado A, Ramírez-Peinado S et al. Sugar-free approaches to cancer cell killing. Oncogene 2011; 30 (3): 253 Oncogene 2011; 30 (3): 253-264. doi: 10.1038/onc.2010.466.

18. Gandini S, Puntoni M, Heckman-Stoddard BM et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila) 2014; 7 (9): 867–885. doi: 10.1158/1940-6207.CAPR-13-0424.

19. Luengo A, Sullivan LB, Heiden MG. Understanding the complex-I-ty of metformin action: limiting mitochondrial respiration to improve cancer therapy. BMC Biol 2014; 12: 82. doi: 10.1186/s12915-014-0082-4.

20. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 2011; 10 (9): 671–684. doi: 10.1038/nrd3504.

21. Sciacovelli M, Frezza C. Oncometabolites: Unconventional triggers of oncogenic signalling cascades. Free Radic Biol Med 2016; 100: 175–181. doi: 10.1016/j.freeradbiomed.2016.04.025.

22. Ward PS, Patel J, Wise DR et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting a-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17 (3): 225–234. doi: 10.1016/j.ccr.2010.01.020.

23. Dang L, White DW, Gross S et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462 (7274): 739–744. doi: 10.1038/nature08617.

24. Chowdhury R, Yeoh KK, Tian Y-M et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 2011; 12 (5): 463–469. doi: 10.1038/embor.2011.43.

25. Xu W, Yang H, Liu Y et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19 (1): 17–30. doi: 10.1016/j.ccr.2010.12.014.

26. Figueroa ME, Abdel-Wahab O, Lu C et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18 (6): 553–567. doi: 10.1016/j.ccr.2010.11.015.

27. Choi C, Ganji SK, DeBerardinis RJ et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 2012; 18 (4): 624–629. doi: 10.1038/nm.2682.

28. Medeiros BC, Fathi AT, DiNardo CD et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 2017; 31 (2): 272–281. doi: 10.1038/leu.2016.275.

29. Wang F, Travins J, DeLaBarre B et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013; 340 (6132): 622–626. doi: 10.1126/science.1234769.

30. Houdová Megová M, Drábek J, Dwight Z et al. Mutace isocitrátdehydrogenázy jsou lepší prognostický marker než metylace promotoru O6-metylguanin-DNA-metyltransferázy u glioblastomů – retrospektivní molekulárně genetická studie gliomů z jednoho centra. Klin Onkol 2017; 30 (5): 361–371. doi: 10.14735/amko2017361.

31. Nassereddine S, Lap CJ, Haroun F et al. The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Ann Hematol 2017; 96 (12): 1983–1991. doi: 10.1007/s00277-017-3161-0.

32. Xiao M, Yang H, Xu W et al. Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 2012; 26 (12): 1326–1338. doi: 10.1101/gad.191056.112.

33. Sullivan LB, Gui DY, Heiden MGV. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Cancer 2016; 16 (11): 680–693. doi: 10.1038/nrc.2016.85.

34. Schito L, Semenza GL. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2016; 2 (12): 758–770. doi: 10.1016/j.trecan.2016.10.016.

35. Kranendijk M, Struys EA, Schaftingen E et al. IDH2 mutations in patients with d-2-hydroxyglutaric aciduria. Science 2010; 330 (6002): 336–336. doi: 10.1126/science.1192632.

36. Schaefer I-M, Hornick JL, Bovée JV. The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology, and molecular mechanisms. Lab Invest 2018; 98 (4): 414–426. doi: 10.1038/s41374-017-0003-6.

37. Fendt SM, Bell EL, Keibler MA et al. Reductive glutamine metabolism is a function of the a-ketoglutarate to citrate ratio in cells. Nat Commun 2013; 4: 2236. doi: 10.1038/ncomms3236.

38. DeBerardinis RJ, Mancuso A, Daikhin E et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci 2007; 104 (49): 19345–19350. doi: 10.1073/pnas.0709747104.

39. DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010; 29 (3): 313–324. doi: 10.1038/onc.2009.358.

40. Wise DR, DeBerardinis RJ, Mancuso A et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci 2008; 105 (48): 18782–18787. doi: 10.1073/pnas.0810199105.

41. Yuneva M, Zamboni N, Oefner P et al. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 2007; 178 (1): 93–105. doi: 10.1083/jcb.200703099.

42. Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene 2016; 35 (28): 3619–3625. doi: 10.1038/onc.2015.447.

43. Gross MI, Demo SD, Dennison JB et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther 2014; 13 (4): 890–901. doi: 10.1158/1535-7163.MCT-13-0870.

44. Ahluwalia GS, Grem JL, Hao Z et al. Metabolism and action of amino acid analog anti-cancer agents. Pharmacol Ther 1990; 46 (2): 243–271.

45. Rais R, Jančařík A, Tenora L et al. Discovery of 6-Diazo-5-oxo- l-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. J Med Chem 2016; 59 (18): 8621–8633. doi: 10.1021/acs.jmedchem.6b01069.

46. Schulte ML, Fu A, Zhao P et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 2018; 24 (2): 194–202. doi: 10.1038/nm.4464.

47. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer 2014; 14 (11): 709–721. doi: 10.1038/nrc3 803.

48. DeNicola GM, Karreth FA, Humpton TJ et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011; 475 (7354): 106–109. doi: 10.1038/nature10189.

49. Low IC, Chen ZX, Pervaiz S. Bcl-2 modulates resveratrol-induced ROS production by regulating mitochondrial respiration in tumor cells. Antioxid Redox Signaling 2010; 13 (6): 807–819. doi: 10.1089/ars.2009.3050.

50. Krishna S, Low IC, and Pervaiz S. Regulation of mitochondrial metabolism: yet another facet in the biology of the oncoprotein Bcl-2. Biochem J 2011; 435: 545–551. doi: 10.1042/BJ20101996.

51. Chong SJ, Low IC, Pervaiz S. Mitochondrial ROS and involvement of Bcl-2 as a mitochondrial ROS regulator. Mitochondrion 2014; 19: 39–48. doi: 10.1016/j.mito.2014.06.002.

52. Weinberg SE, Chandel NS. Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol 2015; 11 (1): 9–15. doi: 10.1038/nchembio.1712.

53. Glorieux C, Calderon PB. Catalase, a remarkable enzyme: targeting the oldest antioxidant enzyme to find a new cancer treatment approach. Biol Chem 2017; 398 (10): 1095–1108. doi: 10.1515/hsz-2017-0131.

54. Magda D, Miller RA. Motexafin gadolinium: A novel redox active drug for cancer therapy. Semin Cancer Biol 2006; 16 (6): 466–476. doi: 10.1016/j.semcancer.2006.09.002.

55. Bey EA, Bentle MS, Reinicke KE et al. An NQO1-and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci U S A 2007; 104 (28): 11832–11837. doi: 10.1073/pnas.0702176104.

56. Tagde A, Singh H, Kang MH et al. The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma. Blood Cancer J 2014; 4: e229. doi: 10.1038/bcj.2014.45.

57. Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci 2009; 100 (1): 9–16. doi: 10.1111/j.1349-7006.2008.01001.x.