3,6-dichloro-1,2,4,5-Tetrazine Assayed at High Doses in the Metastatic Breast Cancer Cell Line MDA-MB-231 Reduces Cell Numbers and Induces Apoptosis

Author(s): Mohamed Abdelkarim*, Khaoula Ben Younes, Ines Limam, Refka Guermazi, Amel Ben Ammaar ElGaaied, Fatma Ben Aissa-Fennira

Journal Name: Current Bioactive Compounds

Volume 16 , Issue 4 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: The lack of treatment options for patients with chemotherapy-resistant cancers is pushing the field toward the development of new therapies. 1,2,4,5-tetrazine derivatives are a class of heterocyclic compounds that exhibit a broad spectrum of antitumor activities.

Objective: The purpose of this study was to assess the biological activity of four s-tetrazine derivatives by substitution of two chloride atom of 3,6-dichloro-1,2,4,5-tetrazine with long hydrophobic side chains.

Methods: We analyzed the anti-proliferative effects of four s-tetrazine derivatives with MTT assay and their pro-apoptotic effect with AV/ IP flow cytometry analysis and Hoechst 33342 staining.

Results: We demonstrated that 3,6-dichloro-1,2,4,5-tetrazine (compound (1)) has a cytotoxic effect and induces apoptosis.

Conclusion: 3,6-dichloro-1,2,4,5-tetrazine presents a new cytotoxic drug against metastatic breast cancer cell line MDA-MB-231 in vitro.

Keywords: 1, 2, 4, 5-tetrazine derivatives, in vitro experiment, MDA-MB-231 cell line, breast cancer, 3, 6-dichloro-1, 2, 4, 5- tetrazine, apoptosis.

[1]
Ginsburg, O.; Bray, F.; Coleman, M.P.; Vanderpuye, V.; Eniu, A.; Kotha, S.R.; Sarker, M.; Huong, T.T.; Allemani, C.; Dvaladze, A.; Gralow, J.; Yeates, K.; Taylor, C.; Oomman, N.; Krishnan, S.; Sullivan, R.; Kombe, D.; Blas, M.M.; Parham, G.; Kassami, N.; Conteh, L. The global burden of women’s cancers: a grand challenge in global health. Lancet, 2017, 389(10071), 847-860.
[http://dx.doi.org/10.1016/S0140-6736(16)31392-7] [PMID: 27814965]
[2]
Shyamasundar, S.; Lim, J.P.; Bay, B.H. miR-93 inhibits the invasive potential of triple-negative breast cancer cells in vitro via protein kinase WNK1. Int. J. Oncol., 2016, 49(6), 2629-2636.
[http://dx.doi.org/10.3892/ijo.2016.3761] [PMID: 27840899]
[3]
Dawood, K.M.; Abdel-Gawad, H.; Ellithey, M.; Mohamed, H.A.; Hegazi, B. Synthesis, anticonvulsant, and anti-inflammatory activities of some new benzofuran-based heterocycles. Arch. Pharm. (Weinheim), 2006, 339(3), 133-140.
[http://dx.doi.org/10.1002/ardp.200500176] [PMID: 16528794]
[4]
Pandey, S.K.; Singh, A.; Singh, A.; Nizamuddin, Antimicrobial studies of some novel quinazolinones fused with [1,2,4]-triazole, [1,2,4]-triazine and [1,2,4,5]-tetrazine rings. Eur. J. Med. Chem., 2009, 44(3), 1188-1197.
[http://dx.doi.org/10.1016/j.ejmech.2008.05.033] [PMID: 18614258]
[5]
Hu, W-X.; Rao, G-W.; Sun, Y-Q. Synthesis and antitumor activity of s-tetrazine derivatives. Bioorg. Med. Chem. Lett., 2004, 14(5), 1177-1181.
[http://dx.doi.org/10.1016/j.bmcl.2003.12.056] [PMID: 14980660]
[6]
Rao, G-W.; Hu, W-X. Synthesis, structure analysis, and antitumor activity of 3,6-disubstituted-1,4-dihydro-1,2,4,5-tetrazine derivatives. Bioorg. Med. Chem. Lett., 2006, 16(14), 3702-3705.
[http://dx.doi.org/10.1016/j.bmcl.2006.04.066] [PMID: 16709456]
[7]
Rao, G-W.; Guo, Y-M.; Hu, W-X. Synthesis, structure analysis, and antitumor evaluation of 3,6-dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide derivatives. ChemMedChem, 2012, 7(6), 973-976.
[http://dx.doi.org/10.1002/cmdc.201200109] [PMID: 22539490]
[8]
Qiu, L-N.; Zhou, Y-L.; Wang, Z-N.; Huang, Q.; Hu, W-X. ZGDHu-1 promotes apoptosis of chronic lymphocytic leukemia cells. Int. J. Oncol., 2012, 41(2), 533-540.
[http://dx.doi.org/10.3892/ijo.2012.1467] [PMID: 22581170]
[9]
Xia, J.; Chen, S-F.; Lv, Y-P.; Lu, L-N.; Hu, W-X.; Zhou, Y-L. ZGDHu-1 induces G2/M phase arrest and apoptosis in Kasumi-1 cells. Mol. Med. Rep., 2015, 11(5), 3398-3404.
[http://dx.doi.org/10.3892/mmr.2015.3160] [PMID: 25573277]
[10]
Chen, S-F.; Xia, J.; Lv, Y-P.; Liu, J-L.; Li, W-X.; Yu, X-P.; Hu, W.X.; Zhou, Y.L. N,N′-di-(m-methylphenyi)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) suppresses the proliferation of PANC-1 pancreatic cancer cells via apoptosis and G2/M cell cycle arrest. Oncol. Rep., 2015, 33(4), 1915-1921.
[http://dx.doi.org/10.3892/or.2015.3803] [PMID: 25683065]
[11]
Qiu, L.; Liu, J.; Wang, Z.; Hu, W.; Huang, Q.; Zhou, Y. ZGDHu-1 and fludarabine have a synergistic effect on apoptosis of chronic lymphocytic leukemia cells. Oncol. Rep., 2015, 34(3), 1239-1248.
[http://dx.doi.org/10.3892/or.2015.4115] [PMID: 26165829]
[12]
Xu, F.; Yang, Z-Z.; Jiang, J-R.; Pan, W-G.; Yang, X.L.; Wu, J-Y.; Zhu, Y.; Wang, J.; Shou, Q.Y.; Wu, H.G. Synthesis, antitumor evaluation and molecular docking studies of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine derivatives. Bioorg. Med. Chem. Lett., 2016, 26(13), 3042-3047.
[http://dx.doi.org/10.1016/j.bmcl.2016.05.007] [PMID: 27184766]
[13]
Shen, X.; Wu, Z.; Chen, S.; Chen, Y.; Xia, J.; Lv, Y.; Zhou, Y. Induction of G2/M phase arrest and apoptosis by ZGDHU-1 in A549 and RERF-LC-MA lung cancer cells. Oncol. Lett., 2016, 12(2), 989-994.
[http://dx.doi.org/10.3892/ol.2016.4697] [PMID: 27446382]
[14]
Guermazi, R.; Clavier, G.; Hedhli, A.; Audebert, P. Functionalization of s-tetrazine: Preparation of new compounds with high synthetic potential. J. Tunisian Chem. Soc., 2016, 18, 8-13.
[15]
Chavez, D.E.; Hiskey, M.A. 1,2,4,5-tetrazine based energetic materials. J. Energ. Mater., 1999, 7(4), 357-377.
[http://dx.doi.org/10.1080/07370659908201796]
[16]
Benson, S.; Lee, L.; Yang, L.; Snyder, J.K. Intramolecular inverse electron demand diels–alder reactions of tryptamine with tethered heteroaromatic azadienes. Tetrahedron, 2000, 56(9), 1165-1180.
[http://dx.doi.org/10.1016/S0040-4020(00)00003-X]
[17]
Han, H.; Long, H.; Wang, H.; Wang, J.; Zhang, Y.; Wang, Z. Progressive apoptotic cell death triggered by transient oxidative insult in H9c2 rat ventricular cells: a novel pattern of apoptosis and the mechanisms. Am. J. Physiol. Heart Circ. Physiol., 2004, 286(6), H2169-H2182.
[http://dx.doi.org/10.1152/ajpheart.00199.2003] [PMID: 14739138]
[18]
Divya, U. Vibha, Sarbjit Singh, Manpreet K. Schiff bases and their metal complexes as anti-cancer agents: A review. Curr. Bioact. Compd., 2015, 11(4), 215-230.
[http://dx.doi.org/10.2174/1573407212666151214221219]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 4
Year: 2020
Published on: 19 June, 2020
Page: [546 - 550]
Pages: 5
DOI: 10.2174/1573407215666181224105826
Price: $65

Article Metrics

PDF: 11
HTML: 1