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Molecular mechanisms of apoptosis induction in K562 and KG1a leukemia cells by a water-soluble copper(II) thiosemicarbazone complex

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Abstract

Thiosemicarbazones (TSCs) and their metal complexes exhibit pronounced and selective cytotoxic potential against a broad span of cancers. Here, we assessed the anti-cancer activity of a water-soluble copper(II) complex of thiosemicarbazone (Cu-TSC) against two cancer cell lines of human leukemia. Our analysis revealed that Cu-TSC treatment results in a time and dose-dependent growth inhibition in K562 and KG1a cells while sparing normal human fibroblast (HFF2) cells. The IC50 values for the Cu-TSC treatment were measured to be 21.7 ± 1.5 µM and 50.25 ± 2.5 µM for K562 and KG1a cells, respectively. Cell cycle analysis indicated that Cu-TSC induces the accumulation of cells in the sub-G1 fraction as well as the reversible arrest in G0/G1 and G2/M phases in K562 and KG1a cells, respectively. Furthermore, the occurrence of apoptosis as the prime mode of cell death was verified through apoptotic body formation, phosphatidylserine externalization, and caspase-3 activation. Additionally, the real-time quantitative PCR analysis revealed that Cu-TSC triggers apoptosis in both cell lines via the upregulation of caspases-8, -9, and the changing of Bax/Bcl2 ratio. Finally, flow cytometric analysis confirmed that Cu-TSC treatment causes the enhancement of reactive oxygen species formation in both K562 and KG1a cells. Altogether, these findings suggest that Cu-TSC is a promising inducer of apoptosis in leukemia cells and carries potential as an anti-cancer compound.

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References

  1. Atasever B, Ülküseven B, Bal-Demirci T, Erdem-Kuruca S, Solakoğlu Z (2010) Invest New Drugs 28(4):421–432

    Article  CAS  PubMed  Google Scholar 

  2. Hancock CN, Stockwin LH, Han B, Divelbiss RD, Jun JH, Malhotra SV, Hollingshead MG, Newton DL (2011) Free Radic Biol Med 50(1):110–121

    Article  CAS  PubMed  Google Scholar 

  3. Pahontu E, Julea F, Rosu T, Purcarea V, Chumakov Y, Petrenco P, Gulea A (2015) J Cell Mol Med 19(4):865–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kalaivani P, Prabhakaran R, Dallemer F, Poornima P, Vaishnavi E, Ramachandran E, Padma VV, Renganathan R, Natarajan K (2012) Metallomics 4(1):101–113

    Article  CAS  PubMed  Google Scholar 

  5. Pervez H, Manzoor N, Yaqub M, Khan KM (2014) J Enzyme Inhib Med Chem 29(5):628–632

    Article  CAS  PubMed  Google Scholar 

  6. Pacca CC, Marques RE, Espindola JWP, Oliveira Filho GBO, Leite ACL, Teixeira MM, Nogueira ML (2017) Biomed Pharmacother 87:381–387

    Article  CAS  PubMed  Google Scholar 

  7. Karaküçük-İyidoğan A, Taşdemir D, Oruç-Emre EE, Balzarini J (2011) Eur J Med Chem 46(11):5616–5624

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Shawish HB, Wong WY, Wong YL, Loh SW, Looi CY, Hassandarvish P, Phan AYL, Wong WF, Wang H, Paterson IC (2014) PLoS ONE 9(6):e100933

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Guo Z-L, Richardson DR, Kalinowski DS, Kovacevic Z, Tan-Un KC, Chan GC (2016) J Hematol Oncol 9(1):1–18

    Article  CAS  Google Scholar 

  10. Hosseini-Yazdi SA, Mirzaahmadi A, Khandar AA, Eigner V, Dušek M, Mahdavi M, Soltani S, Lotfipour F, White J (2017) Polyhedron 124:156–165

    Article  CAS  Google Scholar 

  11. Cabrera M, Gomez N, Lenicov FR, Echeverría E, Shayo C, Moglioni A, Fernández N, Davio C, Chien MH (2015) PLoS ONE 10(9):1–21

    Article  CAS  Google Scholar 

  12. Kolesar J, Brundage RC, Pomplun M, Alberti D, Holen K, Traynor A, Ivy P, Wilding G (2011) Cancer Chemother Pharmacol 67(2):393–400

    Article  CAS  PubMed  Google Scholar 

  13. Kalinowski DS, Stefani C, Toyokuni S, Ganz T, Anderson GJ, Subramaniam NV, Trinder D, Olynyk JK, Chua A, Jansson PJ (2016) Biochim Biophys Acta Mol Cell Res 1863(4):727–748

    Article  CAS  Google Scholar 

  14. Sîrbu A, Palamarciuc O, Babak MV, Lim JM, Ohui K, Enyedy EA, Shova S, Darvasiová D, Rapta P, Ang WH (2017) Dalt Trans 46(12):3833–3847

    Article  CAS  Google Scholar 

  15. Jansson PJ, Kalinowski DS, Lane DJR, Kovacevic Z, Seebacher NA, Fouani L, Sahni S, Merlot AM, Richardson DR (2015) Pharmacol Res 100:255–260

    Article  CAS  PubMed  Google Scholar 

  16. Heffeter P, Pape VFS, Enyedy EA, Keppler BK, Szakas G, Kowol CR (2018) Antioxidants Redox Signal 30(8):1062–1082

    Article  CAS  Google Scholar 

  17. Hager S, Korbula K, Bielec B, Grusch M, Pirker C, Schosserer M, Liendl L, Lang M, Grillari J, Nowikovsky K (2018) Cell Death Dis 9(11):1–17

    Article  CAS  Google Scholar 

  18. Zeglis BM, Divilov V, Lewis JS (2011) J Med Chem 54(7):2391–2398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kasiappan R, Safe SH (2016) React Oxyg Species 1(1):22–37

    Google Scholar 

  20. Myers CR (2016) Free Radic Biol Med 91:81–92

    Article  CAS  PubMed  Google Scholar 

  21. Kalinowski DS, Quach P, Richardson DR (2009) Future 1(6):1143–1151

    CAS  Google Scholar 

  22. Kowol CR, Nagy NV, Jakusch T, Roller A, Heffeter P, Keppler BK, Enyedy ÉA (2015) J Inorg Biochem 152:62–73

    Article  CAS  PubMed  Google Scholar 

  23. Nair RS, Potti ME, Thankappan R, Chandrika SK, Kurup MR, Srinivas P (2017) Mol Carcinog 56(5):1501–1514

    Article  CAS  PubMed  Google Scholar 

  24. Park KC, Fouani L, Jansson PJ, Wooi D, Sahni S, Lane DJR, Palanimuthu D, Lok HC, Kovačević Z, Huang MLH, Kalinowski DS, Richardson DR (2016) Metallomics 8(9):874–886

    Article  CAS  PubMed  Google Scholar 

  25. Taylor MR, Gabe EJ, Glusker JP, Minkin JA, Patterson AL (1966) J Am Chem Soc 88(8):1845–1846

    Article  CAS  PubMed  Google Scholar 

  26. Lisic EC, Rand VG, Ngo L, Kent P, Rice J, Gerlach D, Papish ET, Jiang X (2018) Open J Med Chem 8(02):30–46

    CAS  Google Scholar 

  27. Banerjee K, Basu S, Das S, Sinha A, Biswas MK, Choudhuri SK (2016) Free Radic Res 50(4):426–446

    Article  CAS  PubMed  Google Scholar 

  28. Hosseini-Yazdi SA, Mirzaahmadi A, Khandar AA, Eigner V, Dušek M, Lotfipour F, Mahdavi M, Soltani S, Dehghan G (2017) Inorgan Chim Acta 458:171–180

    Article  CAS  Google Scholar 

  29. Rahimi R, Mahdavi M, Pejman S, Zare P, Balalaei S (2015) Acta Biochim Pol 62(1):83–88

    Article  CAS  PubMed  Google Scholar 

  30. Riccardi C, Nicoletti I (2006) Nat Protoc 1(3):1458–1461

    Article  CAS  PubMed  Google Scholar 

  31. Hasanzadeh D, Mahdavi M, Dehghan G, Charoudeh HN (2017) Toxicol reports 4:420–426

    Article  CAS  Google Scholar 

  32. https://www.bdbiosciences.com/en-us. Accessed June 2019

  33. Ruijter JM, Ramakers C, Hoogaars WMH, Karlen Y, Bakker O, Van den Hoff MJB, Moorman AFM (2009) Nucleic Acids Res 37(6):e45–e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zahedifard M, Faraj FL, Paydar M, Looi CY, Hajrezaei M, Hasanpourghadi M, Kamalidehghan B, Majid NA, Ali HM, Abdulla MA (2015) Sci Rep 5:11544–11561

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Feng Z, Xia Y, Gao T, Xu F, Lei Q, Peng C, Yang Y, Xue Q, Hu X, Wang Q (2018) Cell Death Dis 9(10):1–15

    Google Scholar 

  36. Kovacevic Z, Chikhani S, Lovejoy DB, Richardson DR (2011) Mol Pharmacol 80(4):598–609

    Article  CAS  PubMed  Google Scholar 

  37. Cabrera M, Echeverria E, Lenicov FR, Cardama G, Gonzalez N, Davio C, Fernández N, Lorenzano P (2017) Oncotarget 8(58):98509–98523

    Article  PubMed  PubMed Central  Google Scholar 

  38. Acilan C, Cevatemre B, Adiguzel Z, Karakas D, Ulukaya E, Ribeiro N, Correia I, Pessoa JC (2017) Biochim Biophys Acta Gener Subj 1861(2):218–234

    Article  CAS  Google Scholar 

  39. Fu Y, Liu Y, Wang J, Li CC, Zhou S, Yang Y, Zhou P, Lu C, Li CC (2017) Oncol Rep 37(3):1662–1670

    Article  CAS  PubMed  Google Scholar 

  40. She M, Niu X, Chen X, Li J, Zhou M, He Y, Le Y, Guo K (2012) Cancer Lett 318(2):173–179

    Article  CAS  PubMed  Google Scholar 

  41. Lovejoy DB, Jansson PJ, Brunk UT, Wong J, Ponka P, Richardson DR (2011) Cancer Res 71(17):5871–5880

    Article  CAS  PubMed  Google Scholar 

  42. Redza-Dutordoir M, Averill-Bates DA (2016) Biochim Biophys Acta Mol Cell Res 1863(12):2977–2992

    Article  CAS  Google Scholar 

  43. Kaminskyy VO, Zhivotovsky B (2014) Antioxid Redox Signal 21(1):86–102

    Article  CAS  PubMed  Google Scholar 

  44. Jia G, Wang Q, Wang R, Deng D, Xue L, Shao N, Zhang Y, Xia X, Zhi F, Yang Y (2015) Onco Targets Ther 8:303–311

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Duncan C, White AR (2012) Metallomics 4(2):127–138

    Article  CAS  PubMed  Google Scholar 

  46. Brewer GJ (2005) Drug Discov Today 10(16):1103–1109

    Article  CAS  PubMed  Google Scholar 

  47. Thounaojam TC, Panda P, Mazumdar P, Kumar D, Sharma GD, Sahoo L, Sanjib P (2012) Plant Physiol Biochem 53:33–39

    Article  CAS  PubMed  Google Scholar 

  48. Lee S-Y, Hille A, Kitanovic I, Jesse P, Henze G, Wölfl S, Gust R, Prokop A (2011) Leuk Res 35(3):387–393

    Article  CAS  PubMed  Google Scholar 

  49. Balachandran C, Haribabu J, Jeyalakshmi K, Bhuvanesh NSP, Karvembu R, Emi N, Awale S (2018) J Inorg Biochem 182:208–221

    Article  CAS  PubMed  Google Scholar 

  50. Bisceglie F, Alinovi R, Pinelli S, Galetti M, Pioli M, Tarasconi P, Mutti A, Goldoni M, Pelosi G (2016) Metallomics 8(12):1255–1265

    Article  CAS  PubMed  Google Scholar 

  51. Gutierrez E, Richardson DR, Jansson PJ (2014) J Biol Chem 289(48):33568–33589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Authors would like to express the highest appreciation to the research council of The University of Tabriz, Tabriz, Iran, for supporting this project (which was a part of the Ph.D. thesis).

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Authors and Affiliations

  1. Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

    Fatemeh Ghorbani Parsa, Mohammad Ali Hosseinpour Feizi, Reza Safaralizadeh & Majid Mahdavi

  2. Department of Inorganic Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran

    Seyed Abolfazl Hosseini-Yazdi

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  1. Fatemeh Ghorbani Parsa
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  2. Mohammad Ali Hosseinpour Feizi
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  3. Reza Safaralizadeh
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  4. Seyed Abolfazl Hosseini-Yazdi
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Correspondence to Mohammad Ali Hosseinpour Feizi or Majid Mahdavi.

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Parsa, F.G., Feizi, M.A.H., Safaralizadeh, R. et al. Molecular mechanisms of apoptosis induction in K562 and KG1a leukemia cells by a water-soluble copper(II) thiosemicarbazone complex. J Biol Inorg Chem 25, 383–394 (2020). https://doi.org/10.1007/s00775-020-01769-0

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