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26.10.2016 | PRECLINICAL STUDIES

The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma

verfasst von: Augusto Faria Andrade, Kleiton Silva Borges, Veridiana Kiill Suazo, Lenisa Geron, Carolina Alves Pereira Corrêa, Angel Mauricio Castro-Gamero, Elton José Rosas de Vasconcelos, Ricardo Santos de Oliveira, Luciano Neder, José Andres Yunes, Simone dos Santos Aguiar, Carlos Alberto Scrideli, Luiz Gonzaga Tone

Erschienen in: Investigational New Drugs | Ausgabe 1/2017

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Summary

Medulloblastoma (MB) is the most common solid tumor among pediatric patients and corresponds to 20 % of all pediatric intracranial tumors in this age group. Its treatment currently involves significant side effects. Epigenetic changes such as DNA methylation may contribute to its development and progression. DNA methyltransferase (DNMT) inhibitors have shown promising anticancer effects. The agent Zebularine acts as an inhibitor of DNA methylation and shows low toxicity and high efficacy, being a promising adjuvant agent for anti-cancer chemotherapy. Several studies have reported its effects on different types of tumors; however, there are no studies reporting its effects on MB. We analyzed its potential anticancer effects in four pediatric MB cell lines. The treatment inhibited proliferation and clonogenicity, increased the apoptosis rate and the number of cells in the S phase (p < 0.05), as well as the expression of p53, p21, and Bax, and decreased cyclin A, Survivin and Bcl-2 proteins. In addition, the combination of zebularine with the chemotherapeutic agents vincristine and cisplatin resulted in synergism and antagonism, respectively. Zebularine also modulated the activation of the SHH pathway, reducing SMO and GLI1 levels and one of its targets, PTCH1, without changing SUFU levels. A microarray analysis revealed different pathways modulated by the drug, including the Toll-Like Receptor pathway and high levels of the BATF2 gene. The low expression of this gene was associated with a worse prognosis in MB. Taken together, these data suggest that Zebularine may be a potential drug for further in vivo studies of MB treatment.

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Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109CrossRefPubMedPubMedCentral

Batora NV, Sturm D, Jones DT, Kool M, Pfister SM, Northcott PA (2014) Transitioning from genotypes to epigenotypes: why the time has come for medulloblastoma epigenomics. Neuroscience 264:171–185CrossRefPubMed

Jakacki RI, Burger PC, Zhou T et al (2012) Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's oncology group phase I/II study. J Clin Oncol 30(21):2648–2653CrossRefPubMedPubMedCentral

Northcott PA, Korshunov A, Witt H et al (2011) Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29(11):1408–1414CrossRefPubMed

Taylor MD, Northcott PA, Korshunov A et al (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123(4):465–472CrossRefPubMed

Northcott PA, Jones DT, Kool M et al (2012) Medulloblastomics: the end of the beginning. Nat Rev Cancer 12(12):818–834CrossRefPubMedPubMedCentral

Remke M, Ramaswamy V, Taylor MD (2013) Medulloblastoma molecular dissection: the way toward targeted therapy. Curr Opin Oncol 25(6):674–681CrossRefPubMed

Hovestadt V, Jones DT, Picelli S et al (2014) Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510(7506):537–541CrossRefPubMed

Schwalbe EC, Williamson D, Lindsey JC et al (2013) DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol 125(3):359–371CrossRefPubMedPubMedCentral

10.

Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150(1):12–27CrossRefPubMed

11.

Ecke I, Petry F, Rosenberger A et al (2009) Antitumor effects of a combined 5-aza-2'deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer Res 69(3):887–895CrossRefPubMed

12.

Cheng JC, Yoo CB, Weisenberger DJ et al (2004) Preferential response of cancer cells to zebularine. Cancer Cell 6(2):151–158CrossRefPubMed

13.

Chen M, Shabashvili D, Nawab A et al (2012) DNA methyltransferase inhibitor, zebularine, delays tumor growth and induces apoptosis in a genetically engineered mouse model of breast cancer. Mol Cancer Ther 11(2):370–382CrossRefPubMed

14.

Meador JA, Su Y, Ravanat JL, Balajee AS (2010) DNA-dependent protein kinase (DNA-PK)-deficient human glioblastoma cells are preferentially sensitized by Zebularine. Carcinogenesis 31(2):184–191CrossRefPubMed

15.

Billam M, Sobolewski MD, Davidson NE (2010) Effects of a novel DNA methyltransferase inhibitor zebularine on human breast cancer cells. Breast Cancer Res Treat 120(3):581–592CrossRefPubMed

16.

Nakamura K, Aizawa K, Nakabayashi K et al (2013) DNA methyltransferase inhibitor zebularine inhibits human hepatic carcinoma cells proliferation and induces apoptosis. PLoS One 8(1), e54036CrossRefPubMedPubMedCentral

17.

Andrade AF, Borges KS, Castro-Gamero AM et al (2014) Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells. Anti-Cancer Drugs 25(1):72–81CrossRefPubMed

18.

Ben-Kasus T, Ben-Zvi Z, Marquez VE, Kelley JA, Agbaria R (2005) Metabolic activation of zebularine, a novel DNA methylation inhibitor, in human bladder carcinoma cells. Biochem Pharmacol 70(1):121–133CrossRefPubMed

19.

Tan W, Zhou W, Yu HG, Luo HS, Shen L (2013) The DNA methyltransferase inhibitor zebularine induces mitochondria-mediated apoptosis in gastric cancer cells in vitro and in vivo. Biochem Biophys Res Commun 430(1):250–255CrossRefPubMed

20.

You BR, Park WH (2013) Zebularine-induced apoptosis in Calu-6 lung cancer cells is influenced by ROS and GSH level changes. Tumour Biol 34(2):1145–1153CrossRefPubMed

21.

Yang PM, Lin YT, Shun CT et al (2013) Zebularine inhibits tumorigenesis and stemness of colorectal cancer via p53-dependent endoplasmic reticulum stress. Sci Rep 3:3219PubMedPubMedCentral

22.

Cheng JC, Matsen CB, Gonzales FA et al (2003) Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 95(5):399–409CrossRefPubMed

23.

Liu H, Xue ZT, Sjögren HO, Salford LG, Widegren B (2007) Low dose Zebularine treatment enhances immunogenicity of tumor cells. Cancer Lett 257(1):107–115CrossRefPubMed

24.

Triscott J, Lee C, Foster C et al (2013) Personalizing the treatment of pediatric medulloblastoma: polo-like kinase 1 as a molecular target in high-risk children. Cancer Res 73(22):6734–6744CrossRefPubMed

25.

Borges KS, Moreno DA, Martinelli CE et al (2013) Spindle assembly checkpoint gene expression in childhood adrenocortical tumors (ACT): Overexpression of Aurora kinases A and B is associated with a poor prognosis. Pediatr Blood Cancer 60(11):1809–1816CrossRefPubMed

26.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25(4):402–408CrossRefPubMed

27.

Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58(3):621–681CrossRefPubMed

28.

Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C (2006) Clonogenic assay of cells in vitro. Nat Protoc 1(5):2315–2319CrossRefPubMed

29.

Lim SP, Neilsen P, Kumar R, Abell A, Callen DF (2011) The application of delivery systems for DNA methyltransferase inhibitors. BioDrugs 25(4):227–242CrossRefPubMed

30.

Vousden KH, Lu X (2002) Live or let die: the cell's response to p53. Nat Rev Cancer 2(8):594–604CrossRefPubMed

31.

Girard F, Strausfeld U, Fernandez A, Lamb NJ (1991) Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67(6):1169–1179CrossRefPubMed

32.

Kool M, Jones DT, Jäger N et al (2014) Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25(3):393–405CrossRefPubMedPubMedCentral

33.

Yauch RL, Dijkgraaf GJ, Alicke B et al (2009) Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma. Science 326(5952):572–574CrossRefPubMed

34.

Lin TL, Matsui W (2012) Hedgehog pathway as a drug target: smoothened inhibitors in development. Onco Targets Ther 5:47–58CrossRefPubMedPubMedCentral

35.

Kenney AM, Rowitch DH (2000) Sonic hedgehog promotes G(1) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 20(23):9055–9067CrossRefPubMedPubMedCentral

36.

Kenney AM, Cole MD, Rowitch DH (2003) Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130(1):15–28CrossRefPubMed

37.

You BR, Park WH (2012) Zebularine inhibits the growth of HeLa cervical cancer cells via cell cycle arrest and caspase-dependent apoptosis. Mol Biol Rep 39(10):9723–9731CrossRefPubMed

38.

Deng T, Zhang Y (2009) Possible involvement of activation of P53/P21 and demethylation of RUNX 3 in the cytotoxicity against lovo cells induced by 5-Aza-2'-deoxycytidine. Life Sci 84(9–10):311–320CrossRefPubMed

39.

Karpf AR, Moore BC, Ririe TO, Jones DA (2001) Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2'-deoxycytidine. Mol Pharmacol 59(4):751–757PubMed

40.

Morgan DO (1995) Principles of CDK regulation. Nature 374(6518):131–134CrossRefPubMed

41.

Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2(9):647–656CrossRefPubMed

42.

Tsagarakis NJ, Drygiannakis I, Batistakis AG, Kolios G, Kouroumalis EA (2011) Octreotide induces caspase activation and apoptosis in human hepatoma HepG2 cells. World J Gastroenterol 17(3):313–321CrossRefPubMedPubMedCentral

43.

Wheatley SP, McNeish IA (2005) Survivin: a protein with dual roles in mitosis and apoptosis. Int Rev Cytol 247:35–88CrossRefPubMed

44.

Altieri DC (2008) New wirings in the survivin networks. Oncogene 27(48):6276–6284CrossRefPubMedPubMedCentral

45.

Fangusaro JR, Caldas H, Jiang Y, Altura RA (2006) Survivin: an inhibitor of apoptosis in pediatric cancer. Pediatr Blood Cancer 47(1):4–13CrossRefPubMed

46.

Pizem J, Cört A, Zadravec-Zaletel L, Popovic M (2005) Survivin is a negative prognostic marker in medulloblastoma. Neuropathol Appl Neurobiol 31(4):422–428CrossRefPubMed

47.

Brun SN, Markant SL, Esparza LA et al (2015) Survivin as a therapeutic target in sonic hedgehog-driven medulloblastoma. Oncogene 34(29):3770–3779CrossRefPubMed

48.

Shinwari Z, Manogaran PS, Alrokayan SA, Al-Hussein KA, Aboussekhra A (2008) Vincristine and lomustine induce apoptosis and p21(WAF1) up-regulation in medulloblastoma and normal human epithelial and fibroblast cells. J Neuro-Oncol 87(2):123–132CrossRef

49.

Suzuki M, Shinohara F, Nishimura K, Echigo S, Rikiishi H (2007) Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma. Int J Oncol 31(6):1449–1456PubMed

50.

Berman DM, Karhadkar SS, Hallahan AR et al (2002) Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297(5586):1559–1561CrossRefPubMed

51.

Chari NS, McDonnell TJ (2007) The sonic hedgehog signaling network in development and neoplasia. Adv Anat Pathol 14(5):344–352CrossRefPubMed

52.

Singh RR, Cho-Vega JH, Davuluri Y et al (2009) Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. Cancer Res 69(6):2550–2558CrossRefPubMed

53.

Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087CrossRefPubMed

54.

Katoh Y, Katoh M (2009) Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals. Int J Oncol 35(1):187–192CrossRefPubMed

55.

Shahi MH, Afzal M, Sinha S et al (2010) Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma. BMC Cancer 10:614CrossRefPubMedPubMedCentral

56.

Ma H, Liang X, Chen Y et al (2011) Decreased expression of BATF2 is associated with a poor prognosis in hepatocellular carcinoma. Int J Cancer 128(4):771–777CrossRefPubMed

57.

Su ZZ, Lee SG, Emdad L et al (2008) Cloning and characterization of SARI (suppressor of AP-1, regulated by IFN). Proc Natl Acad Sci U S A 105(52):20906–20911CrossRefPubMedPubMedCentral

58.

Liu Z, Wei P, Yang Y et al (2015) BATF2 deficiency promotes progression in human colorectal cancer via activation of HGF/MET signaling: a potential rationale for combining MET inhibitors with IFNs. Clin Cancer Res 21(7):1752–1763CrossRefPubMed

59.

Roulois D, Loo Yau H, Singhania R et al (2015) DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162(5):961–973CrossRefPubMedPubMedCentral

60.

Chiappinelli KB, Strissel PL, Desrichard A et al (2015) Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162(5):974–986CrossRefPubMedPubMedCentral

Titel: The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma
verfasst von: Augusto Faria Andrade
Kleiton Silva Borges
Veridiana Kiill Suazo
Lenisa Geron
Carolina Alves Pereira Corrêa
Angel Mauricio Castro-Gamero
Elton José Rosas de Vasconcelos
Ricardo Santos de Oliveira
Luciano Neder
José Andres Yunes
Simone dos Santos Aguiar
Carlos Alberto Scrideli
Luiz Gonzaga Tone
Publikationsdatum: 26.10.2016
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 1/2017
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-016-0401-4

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The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma

Summary

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Summary

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