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Cancer Cell International
Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary research

Harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor induces caspase-mediated apoptosis in neuroblastoma

Authors: Katie L. Uhl, Chad R. Schultz, Dirk Geerts, André S. Bachmann

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

Neuroblastoma (NB) is an early childhood malignancy that arises from the developing sympathetic nervous system. Harmine is a tricyclic β-carboline alkaloid isolated from the harmal plant that exhibits both cytostatic and cytotoxic effects. Harmine is capable of blocking the activities of dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family proteins and mitogen-activated protein kinase. These kinases promote proliferation and inhibit apoptosis.

Methods

Four human NB cell lines were used to study the effects of harmine treatment: SKNBE and KELLY (MYCN-amplified) as well as SKNAS and SKNFI (MYCN non-amplified). The anti-cancer properties of harmine were examined by RealTime-Glo MT cell viability assays, caspase activity assays, PARP cleavage using Western blot analysis, and flow cytometry-based Annexin V detection. A molecular interaction model of harmine bound to the DYRK2 family kinase was generated by computational docking using X-ray structures. NB tumors from human patients were profiled for DYRK mRNA expression patterns and clinical correlations using the R2 platform.

Results

The IC50 values for harmine after 72 h treatment were 169.6, 170.8, and 791.7 μM for SKNBE, KELLY, and SKNFI, respectively. Exposure of these NB cell lines to 100 μM of harmine resulted in caspase-3/7 and caspase-9 activation as well as caspase-mediated PARP cleavage and Annexin V-positive stained cells, as early as 24 h after treatment, clearly suggesting apoptosis induction, especially in MYCN-amplified cell lines. Elevated DYRK2 mRNA levels correlated with poor prognosis in a large cohort of NB tumors.

Conclusion

Harmine is a known inhibitor of DYRK family kinases. It can induce apoptosis in NB cell lines, which led us to investigate the clinical correlations of DYRK family gene expression in NB tumors. The patient results support our hypothesis that DYRK inhibition by harmine and the subsequent triggering of caspase-mediated apoptosis might present a novel approach to NB therapy.
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Literature
1.
2.
3.
Moloudizargari M, Mikaili P, Aghajanshakeri S, Asghari MH, Shayegh J. Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids. Pharmacogn Rev. 2013;7:199–212.CrossRefPubMedPubMedCentral
4.
Oliveira CDR, Moreira CQ, de Sá LRM, de Spinosa HS, Yonamine M. Maternal and developmental toxicity of ayahuasca in Wistar rats. Birth Defects Res B Dev Reprod Toxicol. 2010;89:207–12.CrossRefPubMed
5.
Zhang L, Zhang F, Zhang W, Chen L, Gao N, Men Y, et al. Harmine suppresses homologous recombination repair and inhibits proliferation of hepatoma cells. Cancer Biol Ther. 2015;16:1585–92.CrossRefPubMedPubMedCentral
6.
Fortunato JJ, Réus GZ, Kirsch TR, Stringari RB, Stertz L, Kapczinski F, et al. Acute harmine administration induces antidepressive-like effects and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1425–30.CrossRefPubMed
7.
Farouk L, Laroubi A, Aboufatima R, Benharref A, Chait A. Evaluation of the analgesic effect of alkaloid extract of Peganum harmala L.: possible mechanisms involved. J Ethnopharmacol. 2008;115:449–54.CrossRefPubMed
8.
Nenaah G. Antibacterial and antifungal activities of (beta)-carboline alkaloids of Peganum harmala (L) seeds and their combination effects. Fitoterapia. 2010;81:779–82.CrossRefPubMed
9.
Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, et al. Neuroblastoma. Nat Rev Dis Primers. 2016;2:16078.CrossRefPubMed
10.
Himpel S, Panzer P, Eirmbter K, Czajkowska H, Sayed M, Packman LC, et al. Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. Biochem J. 2001;359(Pt 3):497–505.CrossRefPubMedPubMedCentral
11.
12.
13.
Ogawa Y, Nonaka Y, Goto T, Ohnishi E, Hiramatsu T, Kii I, et al. Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nat Commun. 2010;1:86.CrossRefPubMed
14.
Göckler N, Jofre G, Papadopoulos C, Soppa U, Tejedor FJ, Becker W. Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation. FEBS J. 2009;276:6324–37.CrossRefPubMed
15.
16.
Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990;82:1107–12.CrossRefPubMed
17.
Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112–6.CrossRefPubMed
18.
19.
Grosdidier A, Zoete V, Michielin O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res. 2011;39(Web Server issue):W270–7.CrossRefPubMedPubMedCentral
20.
Grosdidier A, Zoete V, Michielin O. Fast docking using the CHARMM force field with EADock DSS. J Comput Chem. 2011;32:2149–59.CrossRefPubMed
21.
Tahtouh T, Elkins JM, Filippakopoulos P, Soundararajan M, Burgy G, Durieu E, et al. Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B. J Med Chem. 2012;55:9312–30.CrossRefPubMed
22.
Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14:27.CrossRef
23.
NCBI Resource Coordinators. Database resources of the national center for biotechnology information. Nucleic Acids Res. 2017;45:D12–7.CrossRef
24.
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10.CrossRefPubMed
25.
Revet I, Huizenga G, Chan A, Koster J, Volckmann R, van Sluis P, et al. The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma. Exp Cell Res. 2008;314:707–19.CrossRefPubMed
26.
27.
Jahaniani F, Ebrahimi SA, Rahbar-Roshandel N, Mahmoudian M. Xanthomicrol is the main cytotoxic component of Dracocephalum kotschyii and a potential anti-cancer agent. Phytochemistry. 2005;66:1581–92.CrossRefPubMed
28.
Atteya R, Ashour ME, Ibrahim EE, Farag MA, El-Khamisy SF. Chemical screening identifies the β-carboline alkaloid harmine to be synergistically lethal with doxorubicin. Mech Ageing Dev. 2017;161:141–8.CrossRefPubMed
29.
Pozo N, Zahonero C, Fernández P, Liñares JM, Ayuso A, Hagiwara M, et al. Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth. J Clin Invest. 2013;123:2475–87.CrossRefPubMedPubMedCentral
30.
Ham J, Costa C, Sano R, Lochmann TL, Sennott EM, Patel NU, et al. Exploitation of the apoptosis-primed state of MYCN-amplified neuroblastoma to develop a potent and specific targeted therapy combination. Cancer Cell. 2016;29:159–72.CrossRefPubMedPubMedCentral
31.
32.
Cuny GD, Robin M, Ulyanova NP, Patnaik D, Pique V, Casano G, et al. Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors. Bioorg Med Chem Lett. 2010;20:3491–4.CrossRefPubMedPubMedCentral
Metadata
Title
Harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor induces caspase-mediated apoptosis in neuroblastoma
Authors
Katie L. Uhl
Chad R. Schultz
Dirk Geerts
André S. Bachmann
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0574-3

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