Ukr.Biochem.J. 2019; Volume 91, Issue 2, Mar-Apr, pp. 29-39

doi: https://doi.org/10.15407/ubj91.02.029

Apoptosis induction in human leukemia cells by novel 2-amino-5-benzylthiazole derivatives

N. S. Finiuk1,2, I. I. Ivasechko1, O. Yu. Klyuchivska1,
Yu. V. Ostapiuk3, V. P. Hreniukh2, Ya. R. Shalai2,
V. S. Matiychuk3, M. D. Obushak3,
A. M. Babsky2, R. S. Stoika1

1Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
2Ivan Franko National University of Lviv, Biology Faculty, Lviv, Ukraine;
3Ivan Franko National University of Lviv, Chemistry Faculty, Lviv, Ukraine;
e-mail: stoika@cellbiol.lviv.ua

Received: 21 December 2018; Accepted: 20 March 2019

Derivatives of 2-amino-5-benzylthiazole are heterocyclic pharmacophores that exhibit different pharmacological activities including anticancer action. The mechanisms of such action of these compounds are not clear. The aim of the present study was to investigate apoptosis induction, particularly DNA damage in human leukemia cells, by the novel synthesized thiazole derivatives ‒ 2,8-dimethyl-7-(3-trifluoromethyl-benzyl)pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one (compound 1) and 7-benzyl-8-methyl-2-propylpyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4(2H)-one (compound 2). Western-blot analysis, DNA comet assay in alkaline conditions, diphenylamine DNA fragmentation assay, agarose gel retardation, and methyl green DNA intercalation assays were used to study the effects of the studied compounds in human leukemia cells. These compounds induced PARP1 and caspase 3 cleavage in the leukemia cells, also increased the level of pro-apoptotic Bim protein and the mitochondrion-specific EndoG nuclease, and decreased the level of the anti-apoptotic Bcl-2 protein. They caused DNA single-strand breaks and DNA fragmentation in the leukemia cells without direct DNA binding or DNA intercalation. Thus, novel 2-amino-5-benzylthiazole derivatives may be promising agents for apoptosis induction in the targeted human leukemia cells.

Keywords: , , , ,


References:

  1. de Santana TI, Barbosa MO, Gomes PATM, da Cruz ACN, da Silva TG, Leite ACL. Synthesis, anticancer activity and mechanism of action of new thiazole derivatives. Eur J Med Chem. 2018 Jan 20;144:874-886. PubMed, CrossRef
  2. Ismail NSM, Ali EMH, Ibrahim DA, Serya RAT, Abou El Ella DA. Pyrazolo[3,4-d]pyrimidine based scaffold derivatives targeting kinases as anticancer agents. Future J Pharmac Sci. 2016; 2(1): 20-30. CrossRef
  3. Sunil D, Isloor AM, Shetty P, Satyamoorthy K, Bharath Prasad AS. 6-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-3-[(2-naphthyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]- thiadiazole as a potent antioxidant and an anticancer agent induces growth inhibition followed by apoptosis in HepG2 cells. Arabian J. Chem. 2010; 3(4): 211-217. CrossRef
  4. Li ZH, Zhang J, Liu XQ, Geng PF, Ma JL, Wang B, Zhao TQ, Zhao B, Wei HM, Wang C, Fu DJ, Yu B, Liu HM. Identification of thiazolo[5,4-d]pyrimidine derivatives as potent antiproliferative agents through the drug repurposing strategy. Eur J Med Chem. 2017 Jul 28;135:204-212. PubMed,CrossRef
  5. Dos Santos TA, da Silva AC, Silva EB, Gomes PA, Espíndola JW, Cardoso MV, Moreira DR, Leite AC, Pereira VR. Antitumor and immunomodulatory activities of thiosemicarbazones and 1,3-Thiazoles in Jurkat and HT-29 cells. Biomed Pharmacother. 2016 Aug;82:555-60. PubMed,CrossRef
  6. Song XJ, Shao Y, Dong XG. Microwave-assisted synthesis of some novel fluorinated pyrazolo[3,4-d]pyrimidine derivatives containing 1,3,4-thiadiazole as potential antitumor agents. Chin Chem Lett. 2011; 22(9): 1036-1038.  CrossRef
  7. Finiuk N. S., Ostapiuk Yu. V., Hreniukh V.P., Shalai Ya. R., Matiychuk V. S., Obushak3 M. D., Stoika R. S., Babsky A. M. Evaluation of antiproliferative activity of pyrazolothiazolopyrimidine derivatives. Ukr Biochem J. 2018; 90(2): 25-32.  CrossRef
  8. Senkiv J, Finiuk N, Kaminskyy D, Havrylyuk D, Wojtyra M, Kril I, Gzella A, Stoika R, Lesyk R. 5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells. Eur J Med Chem. 2016 Jul 19;117:33-46. PubMed, CrossRef
  9. Liao W, McNutt MA, Zhu WG. The comet assay: a sensitive method for detecting DNA damage in individual cells. Methods. 2009 May;48(1):46-53.  PubMed, CrossRef
  10. Finiuk N, Klyuchivska O, Ivasechko I, Hreniukh V, Ostapiuk Y, Shalai Y, Panchuk R, Matiychuk V, Obushak M, Stoika R, Babsky A. Proapoptotic effects of novel thiazole derivative on human glioma cells. Anticancer Drugs. 2019 Jan;30(1):27-37.  PubMed, CrossRef
  11. Arora S, Tandon S. DNA fragmentation and cell cycle arrest: a hallmark of apoptosis induced by Ruta graveolens in human colon cancer cells. Homeopathy. 2015 Jan;104(1):36-47. PubMed, CrossRef
  12. Filak LK, Mühlgassner G, Jakupec MA, Heffeter P, Berger W, Arion VB, Keppler BK. Organometallic indolo[3,2-c]quinolines versus indolo[3,2-d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy. J Biol Inorg Chem. 2010 Aug;15(6):903-18. PubMed, PubMedCentral, CrossRef
  13. Davar D, Beumer JH, Hamieh L, Tawbi H. Role of PARP inhibitors in cancer biology and therapy. Curr Med Chem. 2012;19(23):3907-21. PubMed, PubMedCentral, CrossRef
  14. Zhdanov DD, Fahmi T, Wang X, Apostolov EO, Sokolov NN, Javadov S, Basnakian AG. Regulation of Apoptotic Endonucleases by EndoG. DNA Cell Biol. 2015 May;34(5):316-26. PubMed, PubMedCentral, CrossRef
  15. Kohno M, Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann Med. 2006;38(3):200-11. PubMed, CrossRef
  16. Birnie GD. The HL60 cell line: a model system for studying human myeloid cell differentiation. Br J Cancer Suppl. 1988 Dec;9:41-5. PubMed, PubMedCentral
  17. Klein E, Ben-Bassat H, Neumann H, Ralph P, Zeuthen J, Polliack A, Vánky F. Properties of the K562 cell line, derived from a patient with chronic myeloid leukemia. Int J Cancer. 1976 Oct 15;18(4):421-31. PubMed, CrossRef
  18. Luchetti F, Gregorini A, Papa S, Burattini S, Canonico B, Valentini M, Falcieri E. The K562 chronic myeloid leukemia cell line undergoes apoptosis in response to interferon-alpha. Haematologica. 1998 Nov;83(11):974-80. PubMed
  19. Nitulescu GM, Draghici C, Olaru OT, Matei L, Ioana A, Dragu LD, Bleotu C. Synthesis and apoptotic activity of new pyrazole derivatives in cancer cell lines. Bioorg Med Chem. 2015 Sep 1;23(17):5799-808. PubMed, CrossRef
  20. Prashanth T, Vijay Avin BR, Prabhu Thirusangu, Lakshmi Ranganatha V, Prabhakar BT, Narendra Sharath Chandra JN, Shaukath Ara Khanum. Synthesis of coumarin analogs appended with quinoline and thiazole moiety and their apoptogenic role against murine ascitic carcinoma. Biomed Pharmacother. 2019; 112: 108707. CrossRef
  21. Shahabadi N, Fili SM, Kheirdoosh F. Study on the interaction of the drug mesalamine with calf thymus DNA using molecular docking and spectroscopic techniques. J Photochem Photobiol B. 2013 Nov 5;128:20-6.  PubMed, CrossRef
  22. Palchaudhuri R, Hergenrother PJ. DNA as a target for anticancer compounds: methods to determine the mode of binding and the mechanism of action. Curr Opin Biotechnol. 2007 Dec;18(6):497-503. PubMed, CrossRef
  23. Singla P, Luxami V, Singh R, Tandon V, Paul K. Novel pyrazolo[3,4-d]pyrimidine with 4-(1H-benzimidazol-2-yl)-phenylamine as broad spectrum anticancer agents: Synthesis, cell based assay, topoisomerase inhibition, DNA intercalation and bovine serum albumin studies. Eur J Med Chem. 2017 Jan 27;126:24-35. PubMed, CrossRef
  24. Bera P, Brandao P, Mondal G, Santra A, Jana A, Mokhamatam RB, Kumar Manna S, Mandal TK, Bera P. An unusual iminoacylation of 2-amino pyridyl thiazole: Synthesis, X-ray crystallography and DFT study of copper (II) amidine complexes and their cytotoxicity, DNA binding and cleavage study. Polyhedron. 2019; 159: 436-445. CrossRef
  25. Kaminskyy V, Kulachkovskyy O, Stoika R. A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids. Toxicol Lett. 2008 Apr 1;177(3):168-81.  PubMed, CrossRef
  26. Zheng L, Wang C, Luo T, Lu B, Ma H, Zhou Z, Zhu D, Chi G, Ge P, Luo Y. JNK Activation Contributes to Oxidative Stress-Induced Parthanatos in Glioma Cells via Increase of Intracellular ROS Production. Mol Neurobiol. 2017 Jul;54(5):3492-3505. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.