Nové možnosti starého léku: DHFR- a non-DHFR-mediované účinky metotrexátu na nádorové buňky

English version

Authors: J. Neradil ^1,2; G. Pavlasova ¹; R. Veselska ^1,3
Authors‘ workplace: Laboratory of Tumor Biology, Department of Experimental Biology, School of Science, Masaryk University, Brno, Czech Republic ¹; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic ²; Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Brno, Czech Republic ³
Published in: Klin Onkol 2012; 25(Supplementum 2): 87-92

Práce byla podpořena Evropským fondem pro regionální rozvoj a státním rozpočtem České republiky (OP VaVpI – RECAMO, CZ.1.05/2.1.00/03.0101) a interním projektem Masarykovy univerzity MUNI/C/0803/2011.

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Obdrženo: 1. 10. 2012
Přijato: 6. 11. 2012

Overview

Metotrexát, strukturální analog kyseliny listové, je jedním z nejčastěji používaných chemoterapeutik především pro léčbu hematoonkologických onemocnění, solidních nádorů, ale také některých autoimunitních poruch. Primárně metotrexát narušuje folátový metabolizmus inhibicí dihydrofolátreduktázy, což má za následek potlačení syntézy pyrimidinových a purinových prekurzorů. Nedostatek stavebních kamenů nukleových kyselin se pak odráží v cytostatickém, cytotoxickém a diferenciačním efektu metotrexátu. Mezi další procesy, které jsou ovlivněny inhibicí folátového metabolizmu, patří metylace biomolekul, především proteinů a DNA. Metotrexát však působí na metabolické dráhy a buněčné procesy i nezávisle na metabolizmu folátů. Na základě podobnosti struktury metotrexátu a funkčních skupin některých inhibitorů histondeacetyláz bylo predikováno a poté i experimentálně potvrzeno, že metotrexát má schopnost inhibovat histondeacetylázy. Dále byla prokázána schopnost metotrexátu účinně ovlivňovat glyoxalázový a antioxidační systém. I když je metotrexát používán jako folátový antagonista v protinádorové terapii více než 60 let, odhalování jeho dalších cílů působení na molekulární i buněčné úrovni stále pokračuje.

Klíčová slova:
metotrexát – folátový metabolizmus – dihydrofolátreduktáza – metylace – inhibitory histondeacetylázy – glyoxalázový systém – oxidativní stres

Sources

1. Bartyik K, Turi S, Orosz F et al. Methotrexate inhibits the glyoxalase system in vivo in children with acute lymphoid leukaemia. Eur J Cancer 2004; 40(15): 2287–2292.

2. Huang CC, Hsu PC, Hung YC et al. Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis 2005; 10(4): 895–907.

3. Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 2003; 3(8): 601–614.

4. Assaraf YG. Molecular basis of antifolate resistance. Cancer Metastasis Rev 2007; 26(1): 153–181.

5. Fotoohi AK, Albertioni F. Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells. Leuk Lymphoma 2008; 49(3): 410–426.

6. Genestier L, Paillot R, Quemeneur L et al. Mechanisms of action of methotrexate. Immunopharmacology 2000; 47(2–3): 247–257.

7. Webley SD, Welsh SJ, Jackman AL et al. The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition. Br J Cancer 2001; 85(3): 446–452.

8. Muñoz-Pinedo C, Robledo G, López-Rivas A. Thymidylate synthase inhibition triggers glucose-dependent apoptosis in p53-negative leukemic cells. FEBS Lett 2004; 570(1–3): 205–210.

9. Waldman BC, Wang Y, Kilaru K et al. Induction of intrachromosomal homologous recombination in human cells by raltitrexed, an inhibitor of thymidylate synthase. DNA Repair 2008; 7(10): 1624–1635.

10. Allegra CJ, Hoang K, Yeh GC et al. Evidence for direct inhibition of de novo purine synthesis in human MCF-7 breast cells as a principal mode of metabolic inhibition by methotrexate. J Biol Chem 1987; 262(28): 13520–13526.

11. Allegra CJ, Fine RL, Drake JC et al. The effect of methotrexate on intracellular folate pools in human MCF-7 breast cancer cells. Evidence for direct inhibition of purine synthesis. J Biol Chem 1986; 261(14): 6478–6485.

12. Allegra CJ, Drake JC, Jolivet J et al. Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates. Proc Natl Acad Sci U S A 1985; 82(15): 4881–4885.

13. Baggott JE, Morgan SL, Vaughn WH. Differences in methotrexate and 7-hydroxymethotrexate inhibition of folate-dependent enzymes of purine nucleotide biosynthesis. Biochem J 1994; 300(3): 627–629.

14. Allegra CJ, Chabner BA, Drake JC et al. Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem 1985; 260(17): 9720–9726.

15. McGuire JJ. Anticancer antifolates: current status and future directions. Curr Pharm Des 2003; 9(31): 2593–2613.

16. Genestier L, Paillot R, Fournel S et al. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 1998; 102(2): 322–328.

17. Merkle CJ, Moore IM, Penton BS et al. Methotrexate causes apoptosis in postmitotic endothelial cells. Biol Res Nurs 2000; 2(1): 5–14.

18. Kruman II, Wersto RP, Cardozo-Pelaez F et al. Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 2004; 41(4): 549–561.

19. Bodner AJ, Ting RC, Gallo RC. Induction of differentiation of human promyelocytic leukemia cells (HL-60) by nucleosides and methotrexate. J Natl Cancer Inst 1981; 67(5): 1025–1030.

20. Ross SA, Jones CS, De Luca LM. Retinoic acid and methotrexate specifically increase PHA-E-lectin binding to a 67-kDa glycoprotein in LA-N-1 human neuroblastoma cells. Int J Cancer 1995; 62(3): 303–308.

21. Schwartz PM, Barnett SK, Atillasoy ES et al. Methotrexate induces differentiation of human keratinocytes. Proc Natl Acad Sci U S A 1992; 89(2): 594–598.

22. Seitz M, Zwicker M, Loetscher P. Effects of methotrexate on differentiation of monocytes and production of cytokine inhibitors by monocytes. Arthritis Rheum 1998; 41(11): 2032–2038.

23. Hatse S, Naesens L, De Clercq E et al. Potent differentiation-inducing properties of the antiretroviral agent 9-(2-phosphonylmethoxyethyl) adenine (PMEA) in the rat choriocarcinoma (RCHO) tumor cell model. Biochem Pharmacol 1998; 56(7): 851–859.

24. Hohn HP, Linke M, Denker HW. Adhesion of trophoblast to uterine epithelium as related to the state of trophoblast differentiation: in vitro studies using cell lines. Mol Reprod Dev 2000; 57(2): 135–145.

25. Singh R, Fouladi-Nashta AA, Li D et al. Methotrexate induced differentiation in colon cancer cells is primarily due to purine deprivation. J Cell Biochem 2006; 99(1): 146–155.

26. Serra JM, Gutiérrez A, Alemany R et al. Inhibition of c-Myc down-regulation by sustained extracellular signal-regulated kinase activation prevents the antimetabolite methotrexate- and gemcitabine-induced differentiation in non-small-cell lung cancer cells. Mol Pharmacol 2008; 73(6): 1679–1687.

27. Lin TL, Vala MS, Barber JP et al. Induction of acute lymphocytic leukemia differentiation by maintenance therapy. Leukemia 2007; 21(9): 1915–1920.

28. Hatse S, De Clercq E, Balzarini J. Role of antimetabolites of purine and pyrimidine nucleotide metabolism in tumor cell differentiation. Biochem Pharmacol 1999; 58(4): 539–555.

29. Hara A, Niwa M, Kumada M et al. Intraocular injection of folate antagonist methotrexate induces neuronal differentiation of embryonic stem cells transplanted in the adult mouse retina. Brain Res 2006; 1085(1): 33–42.

30. Hara A, Taguchi A, Aoki H et al. Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina. Neurosci Lett 2010; 477(3): 138–143.

31. Stover PJ. One-carbon metabolism-genome interactions in folate-associated pathologies. J Nutr 2009; 139(12): 2402–2405.

32. Vezmar S, Schüsseler P, Becker A et al. Methotrexate-associated alterations of the folate and methyl-transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity. Pediatr Blood Cancer 2009; 52(1): 26–32.

33. Li M, Hu SL, Shen ZJ et al. High-performance capillary electrophoretic method for the quantification of global DNA methylation: application to methotrexate-resistant cells. Anal Biochem 2009; 387(1): 71–75.

34. Wang YC, Chiang EP. Low-dose methotrexate inhibits methionine S-adenosyltransferase in vitro and in vivo. Mol Med 2012; 18(1): 423–432.

35. Winter-Vann AM, Kamen BA, Bergo MO et al. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc Natl Acad Sci U S A 2003; 100(11): 6529–6534.

36. Wu J, Wood GS. Reduction of Fas/CD95 promoter methylation, upregulation of Fas protein, and enhancement of sensitivity to apoptosis in cutaneous T-cell lymphoma. Arch Dermatol 2011; 147(4): 443–449.

37. Salbaum JM, Kappen C. Genetic and epigenomic footprints of folate. Prog Mol Biol Transl Sci 2012; 108: 129–158.

38. Mahoney SE, Yao Z, Keyes CC et al. Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas. Epigenetics 2012; 7(4): 400–408.

39. Diede SJ, Guenthoer J, Geng LN et al. DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences. Proc Natl Acad Sci U S A 2010; 107(1): 234–239.

40. Restrepo A, Smith CA, Agnihotri S et al. Epigenetic regulation of glial fibrillary acidic protein by DNA methylation in human malignant gliomas. Neuro Oncol 2011; 13(1): 42–50.

41. Hill VK, Underhill-Day N, Krex D et al. Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis. Oncogene 2011; 30(8): 978–989.

42. Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 2002; 21(35): 5427–5440.

43. Yang PM, Lin JH, Huang WY et al. Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate. Biochem Biophys Res Commun 2010; 391(3): 1396–1399.

44. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 2007; 26(37): 5541–5552.

45. Marks PA, Xu WS. Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem 2009; 107(4): 600–608.

46. Huang WY, Yang PM, Chang YF et al. Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2. Biochem Pharmacol 2011; 81(4): 510–517.

47. Chang CJ, Hung MC. The role of EZH2 in tumour progression. Br J Cancer 2012; 106(2): 243–247.

48. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5(9): 769–784.

49. Dell’Aversana C, Lepore I, Altucci L. HDAC modulation and cell death in the clinic. Exp Cell Res 2012; 318(11): 1229–1244.

50. Leclerc GJ, Mou C, Leclerc GM et al. Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy. Leukemia 2010; 24(3): 552–562.

51. Einsiedel HG, Kawan L, Eckert C et al. Histone deacetylase inhibitors have antitumor activity in two NOD/SCID mouse models of B-cell precursor childhood acute lymphoblastic leukemia. Leukemia 2006; 20(8): 1435–1436.

52. Bastian L, Einsiedel HG, Henze G et al. The sequence of application of methotrexate and histone deacetylase inhibitors determines either a synergistic or an antagonistic response in childhood acute lymphoblastic leukemia cells. Leukemia 2011; 25(2): 359–361.

53. Prasad P, Vasquez H, Das CM et al. Histone acetylation resulting in resistance to methotrexate in choroid plexus cells. J Neurooncol 2009; 91(3): 279–286.

54. Thornalley PJ, Rabbani N. Glyoxalase in tumourigenesis and multidrug resistance. Semin Cell Dev Biol 2011; 22(3): 318–325.

55. Santarius T, Bignell GR, Greenman CD et al. GLO1-A novel amplified gene in human cancer. Genes Chromosomes Cancer 2010; 49(8): 711–725.

56. Suji G, Sivakami S. DNA damage during glycation of lysine by methylglyoxal: assessment of vitamins in preventing damage. Amino Acids 2007; 33(4): 615–621.

57. Pepper ED, Farrell MJ, Nord G et al. Antiglycation effects of carnosine and other compounds on the long-term survival of Escherichia coli. Appl Environ Microbiol 2010; 76(24): 7925–7930.

58. Kalapos MP. The tandem of free radicals and methylglyoxal. Chem Biol Interact 2008; 171(3): 251–271.

59. Koizumi K, Nakayama M, Zhu WJ et al. Characteristic effects of methylglyoxal and its degraded product formate on viability of human histiocytes: a possible detoxification pathway of methylglyoxal. Biochem Biophys Res Commun 2011; 407(2): 426–431.

60. Uzar E, Koyuncuoglu HR, Uz E et al. The activities of antioxidant enzymes and the level of malondialdehyde in cerebellum of rats subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem 2006; 291(1–2): 63–68.

61. Miketova P, Kaemingk K, Hockenberry M et al. Oxidative changes in cerebral spinal fluid phosphatidylcholine during treatment for acute lymphoblastic leukemia. Biol Res Nurs 2005; 6(3): 187–195.

62. Jahovic N, Cevik H, Sehirli AO et al. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res 2003; 34(4): 282–287.

63. Caetano NN, Campello AP, Carnieri EG et al. Effect of methotrexate (MTX) on NAD(P)+ dehydrogenases of HeLa cells: malic enzyme, 2-oxoglutarate and isocitrate dehydrogenases. Cell Biochem Funct 1997; 15(4): 259–264.

64. Babiak RM, Campello AP, Carnieri EG et al. Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct 1998; 16(4): 283–293.

65. Vardi N, Parlakpinar H, Ates B. Beneficial effects of chlorogenic acid on methotrexate-induced cerebellar Purkinje cell damage in rats. J Chem Neuroanat 2012; 43(1): 43–47.

66. Spurlock CF 3rd, Aune ZT, Tossberg JT et al. Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. Arthritis Rheum 2011; 63(9): 2606–2616.

67. Zapletalova D, André N, Deak L et al. Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience. Oncology 2012; 82(5): 249–260.

68. Carrasco MP, Enyedy EA, Krupenko NI et al. Novel folate-hydroxamate based antimetabolites: synthesis and biological evaluation. Med Chem 2011; 7(4): 265–274.

69. Zimmermann GR, Lehár J, Keith CT. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today 2007; 12(1–2): 34–42.