Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Letter Article

The DNMT3B Inhibitor Nanaomycin A as a Neuroblastoma Therapeutic Agent

Author(s): Kazuya Izumi, Hiromasa Aoki, Hiroki Kakita, Satoru Takeshita, Hiroko Ueda, Yasumichi Inoue, Hidetoshi Hayashi, Yasumasa Yamada and Mineyoshi Aoyama*

Volume 23, Issue 11, 2023

Published on: 13 June, 2023

Page: [837 - 842] Pages: 6

DOI: 10.2174/1568009623666230522113645

Price: $65

Abstract

Background: Neuroblastoma is one of the most common childhood solid tumors. Because tumor suppressor genes are often hypermethylated in cancers, DNA methylation has emerged as a target for cancer therapeutics. Nanaomycin A, an inhibitor of DNA methyltransferase 3B, which mediates de novo DNA methylation, reportedly induces death in several types of human cancer cells.

Objective: To study the antitumor activity of nanaomycin A against neuroblastoma cell lines and its mechanism.

Methods: The anti-tumor effect of nanaomycin A on neuroblastoma cell lines was evaluated based on cell viability, DNA methylation levels, apoptosis-related protein expression, and neuronal-associated mRNA expression.

Results: Nanaomycin A decreased genomic DNA methylation levels and induced apoptosis in human neuroblastoma cells. Nanaomycin A also upregulated the expression of mRNAs for several genes related to neuronal maturation.

Conclusions: Nanaomycin A is an effective therapeutic candidate for treating neuroblastoma. Our findings also suggest that the inhibition of DNA methylation is a promising anti-tumor therapy strategy for neuroblastoma.

Keywords: Neuroblastoma, DNA methylation, epigenetics, DNA methyltransferase 3B, nanaomycin A, apoptosis.

Graphical Abstract
[1]
Nakagawara, A.; Li, Y.; Izumi, H.; Muramori, K.; Inada, H.; Nishi, M. Neuroblastoma. Jpn. J. Clin. Oncol., 2018, 48(3), 214-241.
[http://dx.doi.org/10.1093/jjco/hyx176] [PMID: 29378002]
[2]
Matthay, K.K.; Maris, J.M.; Schleiermacher, G.; Nakagawara, A.; Mackall, C.L.; Diller, L.; Weiss, W.A. Neuroblastoma. Nat. Rev. Dis. Primers, 2016, 2(1), 16078.
[http://dx.doi.org/10.1038/nrdp.2016.78] [PMID: 27830764]
[3]
Tsubota, S.; Kadomatsu, K. Origin and initiation mechanisms of neuroblastoma. Cell Tissue Res., 2018, 372(2), 211-221.
[http://dx.doi.org/10.1007/s00441-018-2796-z] [PMID: 29445860]
[4]
Takita, J. Molecular basis and clinical features of neuroblastoma. Japan Med. Assoc. J., 2021, 4(4), 321-331.
[PMID: 34796286]
[5]
Jones, P.A. Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat. Rev. Genet., 2012, 13(7), 484-492.
[http://dx.doi.org/10.1038/nrg3230] [PMID: 22641018]
[6]
Moore, L.D.; Le, T.; Fan, G. DNA methylation and its basic function. Neuropsychopharmacology, 2013, 38(1), 23-38.
[http://dx.doi.org/10.1038/npp.2012.112] [PMID: 22781841]
[7]
Okano, M.; Bell, D.W.; Haber, D.A.; Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell, 1999, 99(3), 247-257.
[http://dx.doi.org/10.1016/S0092-8674(00)81656-6] [PMID: 10555141]
[8]
Klutstein, M.; Nejman, D.; Greenfield, R.; Cedar, H. DNA methylation in cancer and aging. Cancer Res., 2016, 76(12), 3446-3450.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-3278] [PMID: 27256564]
[9]
Ram Kumar, R.M.; Schor, N.F. Methylation of DNA and chromatin as a mechanism of oncogenesis and therapeutic target in neuroblastoma. Oncotarget, 2018, 9(31), 22184-22193.
[http://dx.doi.org/10.18632/oncotarget.25084] [PMID: 29774131]
[10]
Gröbner, S.N.; Worst, B.C.; Weischenfeldt, J.; Buchhalter, I.; Kleinheinz, K.; Rudneva, V.A.; Johann, P.D.; Balasubramanian, G.P.; Segura-Wang, M.; Brabetz, S.; Bender, S.; Hutter, B.; Sturm, D.; Pfaff, E.; Hübschmann, D.; Zipprich, G.; Heinold, M.; Eils, J.; Lawerenz, C.; Erkek, S.; Lambo, S.; Waszak, S.; Blattmann, C.; Borkhardt, A.; Kuhlen, M.; Eggert, A.; Fulda, S.; Gessler, M.; Wegert, J.; Kappler, R.; Baumhoer, D.; Burdach, S.; Kirschner-Schwabe, R.; Kontny, U.; Kulozik, A.E.; Lohmann, D.; Hettmer, S.; Eckert, C.; Bielack, S.; Nathrath, M.; Niemeyer, C.; Richter, G.H.; Schulte, J.; Siebert, R.; Westermann, F.; Molenaar, J.J.; Vassal, G.; Witt, H.; Burkhardt, B.; Kratz, C.P.; Witt, O.; van Tilburg, C.M.; Kramm, C.M.; Fleischhack, G.; Dirksen, U.; Rutkowski, S.; Frühwald, M.; von Hoff, K.; Wolf, S.; Klingebiel, T.; Koscielniak, E.; Landgraf, P.; Koster, J.; Resnick, A.C.; Zhang, J.; Liu, Y.; Zhou, X.; Waanders, A.J.; Zwijnenburg, D.A.; Raman, P.; Brors, B.; Weber, U.D.; Northcott, P.A.; Pajtler, K.W.; Kool, M.; Piro, R.M.; Korbel, J.O.; Schlesner, M.; Eils, R.; Jones, D.T.W.; Lichter, P.; Chavez, L.; Zapatka, M.; Pfister, S.M. The landscape of genomic alterations across childhood cancers. Nature, 2018, 555(7696), 321-327.
[http://dx.doi.org/10.1038/nature25480] [PMID: 29489754]
[11]
Ma, X.; Liu, Y.; Liu, Y.; Alexandrov, L.B.; Edmonson, M.N.; Gawad, C.; Zhou, X.; Li, Y.; Rusch, M.C.; Easton, J.; Huether, R.; Gonzalez-Pena, V.; Wilkinson, M.R.; Hermida, L.C.; Davis, S.; Sioson, E.; Pounds, S.; Cao, X.; Ries, R.E.; Wang, Z.; Chen, X.; Dong, L.; Diskin, S.J.; Smith, M.A.; Guidry, A.J.M.; Meltzer, P.S.; Lau, C.C.; Perlman, E.J.; Maris, J.M.; Meshinchi, S.; Hunger, S.P.; Gerhard, D.S.; Zhang, J. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature, 2018, 555(7696), 371-376.
[http://dx.doi.org/10.1038/nature25795] [PMID: 29489755]
[12]
Baylin, S.B.; Jones, P.A. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol., 2016, 8(9), a019505.
[http://dx.doi.org/10.1101/cshperspect.a019505] [PMID: 27194046]
[13]
Ma, J.; Ge, Z. Comparison between decitabine and azacitidine for patients with acute myeloid leukemia and higher-risk myelodysplastic syndrome: A systematic review and network meta-analysis. Front. Pharmacol., 2021, 12, 701690.
[http://dx.doi.org/10.3389/fphar.2021.701690] [PMID: 34483903]
[14]
George, R.E.; Lahti, J.M.; Adamson, P.C.; Zhu, K.; Finkelstein, D.; Ingle, A.M.; Reid, J.M.; Krailo, M.; Neuberg, D.; Blaney, S.M.; Diller, L. Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: A children’s oncology group study. Pediatr. Blood Cancer, 2010, 55(4), 629-638.
[http://dx.doi.org/10.1002/pbc.22607] [PMID: 20589651]
[15]
Kuck, D.; Caulfield, T.; Lyko, F.; Medina-Franco, J.L. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Mol. Cancer Ther., 2010, 9(11), 3015-3023.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0609] [PMID: 20833755]
[16]
Kanda, Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant., 2013, 48(3), 452-458.
[http://dx.doi.org/10.1038/bmt.2012.244] [PMID: 23208313]
[17]
Hua, Z.; Gu, X.; Dong, Y.; Tan, F.; Liu, Z.; Thiele, C.J.; Li, Z. PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma. Tumour Biol., 2016, 37(12), 16227-16236.
[http://dx.doi.org/10.1007/s13277-016-5433-z] [PMID: 27752996]
[18]
Matthay, K.K.; Villablanca, J.G.; Seeger, R.C.; Stram, D.O.; Harris, R.E.; Ramsay, N.K.; Swift, P.; Shimada, H.; Black, C.T.; Brodeur, G.M.; Gerbing, R.B.; Reynolds, C.P. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N. Engl. J. Med., 1999, 341(16), 1165-1173.
[http://dx.doi.org/10.1056/NEJM199910143411601] [PMID: 10519894]
[19]
Penter, L.; Maier, B.; Frede, U.; Hackner, B.; Carell, T.; Hagemeier, C.; Truss, M. A rapid screening system evaluates novel inhibitors of DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk neuroblastoma. Target. Oncol., 2015, 10(4), 523-533.
[http://dx.doi.org/10.1007/s11523-014-0354-5] [PMID: 25559288]
[20]
Gagliardi, M.; Strazzullo, M.; Matarazzo, M.R. DNMT3B Functions: Novel insights from human disease. Front. Cell Dev. Biol., 2018, 6, 140.
[http://dx.doi.org/10.3389/fcell.2018.00140] [PMID: 30406101]
[21]
Zhang, Y.; Charlton, J.; Karnik, R.; Beerman, I.; Smith, Z.D.; Gu, H.; Boyle, P.; Mi, X.; Clement, K.; Pop, R.; Gnirke, A.; Rossi, D.J.; Meissner, A. Targets and genomic constraints of ectopic Dnmt3b expression. eLife, 2018, 7, e40757.
[http://dx.doi.org/10.7554/eLife.40757] [PMID: 30468428]
[22]
Smith, V.; Foster, J. High-risk neuroblastoma treatment review. Children, 2018, 5(9), 114.
[http://dx.doi.org/10.3390/children5090114] [PMID: 30154341]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy