Skip to main content

Advertisement

SpringerLink
Log in

MDR1 and Cytochrome P450 Gene-Expression Profiles as Markers of Chemosensitivity in Human Chronic Myelogenous Leukemia Cells Treated with Cisplatin and Ru(III) Metallocomplexes

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Leukemia is a major type of cancer affecting a significant segment of the population, and especially children. In fact, leukemia is the most frequent childhood cancer, with 26 % of all cases, and 20 % mortality. The multidrug resistance phenotype (MDR) is considered one of the major causes of failure in cancer chemotherapy. The present study aimed to investigate the relationship between the expression of MDR1 and CYP450 genes in human chronic myelogenous leukemia cells (K-562) treated with cisplatin (cisPt) and two ruthenium-based coordinated complexes [cisCRu(III) and cisDRu(III)]. The tested compounds induced apoptosis in K-562 tumor cells as evidenced by caspase 3 activation. Results also revealed that the amplification of P-gp gene is greater in K-562 cells exposed to cisPt and cisCRu(III) than cisDRu(III). Taken together, all these results strongly demonstrate that MDR-1 overexpression in K-562 cells could be associated to a MDR phenotype, and moreover, it is also contributing to the platinum and structurally related compound, resistance in these cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Pereira FC, Lima AP, Vilanova-Costa CAST, Pires WCP, Ribeiro ASBB, Pereira LCG, Pavanin LA, dos Santos WB, Silveira-Lacerda EP (2014) Cytotoxic effects of the compound cis-tetraammine(oxalato)ruthenium(III) dithionate on K-562 human chronic myelogenous leukemia cells. Springer Plus 3:301

    Article  PubMed Central  PubMed  Google Scholar 

  2. Deininger MW (2008) Chronic myeloid leukemia: a historical perspective. American Society of Hematology Education Program Book, 50th Anniversary Review 418

  3. Srabanti R, Jayashree B, Labanya M, Kausik P, Dipyaman G, Sandip B, Monidipa G, Nabendu B, Utpal C, Santu B (2009) N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide. Apoptosis 14:298–308

    Article  Google Scholar 

  4. Deininger MWN, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96:3343–3356

    CAS  PubMed  Google Scholar 

  5. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV (2003) MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101(6):2368–2373

    Article  CAS  PubMed  Google Scholar 

  6. Runge D, Kohler C, Kostrubsky VE, Jager D, Lehmann T, Runge DM, May U, Stolz DB, Strom SC, Fleig WE, Michalopoulos GK (2000) Induction of cytochrome P450 (CYP)1A1, CYP1A2, and CYP3A4 but not of CYP2C9, CYP2C19, multidrug resistance (MDR-1) and multidrug resistance associated protein (MRP-1) by prototypical inducers in human hepatocytes. Biochem Biophys Res Commun 273:333–341

    Article  CAS  PubMed  Google Scholar 

  7. Coburger C, Lage H, Molnár J, Hilgeroth A (2009) Impact of novel MDR modulators on human cancer cells: reversal activities and induction studies. Pharm Res 26(1)

  8. Assef Y, Rubio F, Coló G, del Mónaco S, Costas MA, Kotsias BA (2009) Imatinib resistance in multidrug-resistant K562 human leukemic cells. Leuk Res 33(5):710–716

    Article  CAS  PubMed  Google Scholar 

  9. Alama A, Tasso B, Novelli F, Sparatore F (2009) Organometallic compound in oncology: implications of novel organotins as antitumor agents. Drug Discov Today 14:500–508

    Article  CAS  PubMed  Google Scholar 

  10. Dorcier A, Ang WH, Bolaño S, Gonsalvi L, Juillerat-Jeannerat L, Laurenczy G, Peruzzini M, Phillips AD, Zanobini F, Dyson PJ (2006) In vitro evaluation of rhodium and osmium RAPTA analogues: the case for organometallic anticancer drugs not based on ruthenium. Organometallics 25:4090–4096

    Article  CAS  Google Scholar 

  11. Stordal B, Pavlakis N, Davey R (2007) A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship. Cancer Treat Rev 33(8):688–703

    Article  CAS  PubMed  Google Scholar 

  12. Jirsova K, Mandys V, Gispen WH, Bar PR (2006) Cisplatin-induced apoptosis in cultures of human Schwann cell. Neurosci Lett 392:22–26

    Article  CAS  PubMed  Google Scholar 

  13. Sava G, Bergamo A (2000) Ruthenium-based compounds and tumour growth control (review). Int J Oncol 17:353–365

    CAS  PubMed  Google Scholar 

  14. Vock CA, Ang WH, Scolaro C, Phillips AD, Lagopoulos L, Juillerat-Jeanneret L, Sava G, Scopelliti R, Dyson PJ (2007) Development of ruthenium antitumor drugs that overcome multidrug resistance mechanisms. J Med Chem 50(9):2166–2175

    Article  CAS  PubMed  Google Scholar 

  15. Pavanin LA, Giesbrecht E, Tfouni E (1985) Synthesis and properties of the ruthenium(II) complexes cis-Ru(NH3)4(isn)L2+ spectra and reduction potentials. Inorg Chem 24:4444–4446

    Article  CAS  Google Scholar 

  16. Pereira FC, Vilanova-Costa CAST, Lima AP, Ribeiro ASBB, da Silva HD, Pavanin LA, Silveira-Lacerda EP (2009) Cytotoxic and genotoxic effects of cis-tetraammine(oxalato)ruthenium(III) dithionate on the root meristem cells of Allium cepa. Biol Trace Elem Res 128(3):258–268

    Article  CAS  Google Scholar 

  17. Silveira-Lacerda EP, Vilanova-Costa CAST, Pereira FC, Hamaguchi A, Pavanin LA, Goulart LR, Homsi-Brandenburgo MI, Santos WB, Soares AM, Nomizo A (2010) The ruthenium complex cis-(dichloro)tetraammineruthenium(III) chloride presents immune stimulatory activity on human peripheral blood mononuclear cells. Biol Trace Elem Res 133:270–283

    Article  CAS  Google Scholar 

  18. Mosman T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 16:55–63

    Article  Google Scholar 

  19. Lobner D (2000) Comparison of the LDH and MTT assays for quantifying cell death: validity for neuronal apoptosis. J Neurosci Methods 96:147–152

    Article  CAS  PubMed  Google Scholar 

  20. Alderden RA, Mellor HR, Modok S, Hambley TW, Callaghan R (2006) Cytotoxic efficacy of an anthraquinone linked platinum anticancer drug. Biochem Pharmacol 71:1136–1145

    Article  CAS  PubMed  Google Scholar 

  21. Zhang CX, Lippard SJ (2003) New metal complexes as potential therapeutics. Curr Opin Chem Biol 7(4):481–489

    Article  CAS  PubMed  Google Scholar 

  22. Ang WH, Khalaila I, Allardyce CS, Juillerat-Jeanneret L, Dyson PJ (2005) Rational design of platinum(IV) compounds to overcome glutathione-S-transferase mediated drug resistance. J Am Chem Soc 127:1382–1383

    Article  CAS  PubMed  Google Scholar 

  23. Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33

    Article  CAS  PubMed  Google Scholar 

  24. Fischer V, Einolf HJ, Cohen D (2005) Efflux transporters and their clinical relevance. Min Rev Med Chem 5:183–195

    Article  CAS  Google Scholar 

  25. Goldstein JA (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 52:349–355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Rodriguez-Antona C, Ingelman-Sundberg M (2006) Cytochrome P450 pharmacogenetics and cancer. Oncogene 25:1679–1691

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka E (1999) Update: genetic polymorphism of drug metabolizing enzymes in humans. J Clin Pharm Ther 24:323–329

    Article  CAS  PubMed  Google Scholar 

  28. Tsuneoka Y, Fukushima K, Matsuo Y, Ichikawa Y, Watanabe Y (1996) Genotype analysis of the CYP2C19 gene in the Japanese population. Life Sci 59:1711–1715

    Article  CAS  PubMed  Google Scholar 

  29. Xing SW, Qing CS (2004) Frequencies of poor metabolizers of cytochrome P450 2C19 in esophagus cancer, stomach cancer, lung cancer and bladder cancer in Chinese population. World J Gastroenterol 10:1961–1963

    Google Scholar 

  30. Yoshiyuki Y, Ken-ichi F, Nakayama K, Suzuki A, Nakamura K, Yamazaki H, Kamataki T (2004) Establishment of ten strains of genetically engineered Salmonella typhimurium TA1538 each co-expressing a form of human cytochrome P450 with NADPH-cytochrome P450 reductase sensitive to various promutagens. Mutat Res 562:151–162

    Article  Google Scholar 

  31. Menezes CSR, Gebrim LC, Ávila VMR, Ferreira MJ, Vieira CU, Pavanin LA, Homsi-brandeburgo MI, Hamaguchi A, Silveira-Lacerda EP (2007) Analysis in vivo of antitumor activity, cytotoxicity and interaction between plasmid DNA and the cis-dichlorotetramineruthenium(III) chloride. Chem Biol Interact 167:116–124

    Article  CAS  PubMed  Google Scholar 

  32. Wyllie AH, Kerr JFR, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251–306

    Article  CAS  PubMed  Google Scholar 

  33. Silveira-Lacerda EP, Vilanova-Costa C, Hamaguchi A, Pavanin LA, Goulart LR, Homsi-brandeburgo MI, Santos WB, Soares AM, Nomizo A (2010) The ruthenium complex cis-(dichloro)tetraammineruthenium(III) chloride presents selective cytotoxicity against murine B cell lymphoma (A-20), murine ascitic sarcoma 180 (S-180), human breast adenocarcinoma (SK-BR-3), and human T cell leukemia (Jurkat) tumor cell lines. Biol Trace Elem Res 135:98–111

    Article  CAS  Google Scholar 

  34. Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326:1–16

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256(1):42–49

    Article  CAS  PubMed  Google Scholar 

  36. Kaufmann SH, Hengartner MO (2001) Programmed cell death: alive and well in the new millennium. Trends Cell Biol 11(12):526–534

    Article  CAS  PubMed  Google Scholar 

  37. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nature 5:876–885

    CAS  Google Scholar 

  38. Shi Y (2002) Mechanisms of caspase activation and inhibition during poptosis. Mol Cell 9:459–470

    Article  CAS  PubMed  Google Scholar 

  39. Kapitza S, Jakupec MA, Uhl M, Keppler BK, Marian B (2005) The heterocyclic ruthenium(III) complex KP1019 (FFC14A) causes DNA damage and oxidative stress in colorectal tumor cells. Cancer Lett 226:115–121

    Article  CAS  PubMed  Google Scholar 

  40. Chatterjee S, Kundu S, Bhattacharya A, Christian G, Hartinger CG, Dyson PJ (2008) The ruthenium(II)–arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53–JNK pathways. JBIC J Biol Inorg Chem 13:1149–1155

    Article  CAS  Google Scholar 

  41. Vilanova-Costa CAST, Porto HKP, Pereira FC, Lima AP, dos Santos WB, Silveira-Lacerda EP (2014) The ruthenium complexes cis-(dichloro)tetramineruthenium(III) chloride and cis-tetraammine(oxalato)ruthenium(III) dithionate overcome resistance inducing apoptosis on human lung carcinoma cells (A549). Biometals 27:459–469

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge the financial support of Research and Projects Financing (FINEP) (Grant No. 01.06.0941.00/CT-Saúde to Elisângela de Paula Silveira-Lacerda) and Foundation for the Support of Research in the State of Goias (FAPEG). Coordination for the Advancement of Higher Education Staff (CAPES) through fellowship to Cesar Augusto Sam Tiago Vilanova-Costa, Hellen Karine Paes Porto and Lucas Carlos Gomes Pereira.

Funding Sources

There are no financial or personal interests that might be viewed as inappropriate influences on the work presented herein. This manuscript was completely financed by governmental and nonprofit institutions, the Brazilian National Counsel of Technological and Scientific Development (CNPq), Research and Projects Financing (FINEP), Coordination for the Advancement of Higher Education Staff (CAPES), and Foundation for the Support of Research in the State of Goias (FAPEG).

Ethical Approval

No studies involving humans or experimental animals were conducted in this work. The human chronic myelogenous leukemia K-562 cells were purchased from the American Type Culture Collection (ATCC, Rockville, MD, USA) and cultured in vitro.

Author information

Authors and Affiliations

  1. Laboratório de Genética Molecular e Citogenética, Instituto de Ciências Biológicas - ICB, Universidade Federal de Goiás - UFG, Campus Samambaia (Campus II), Cx. Postal: 131, Goiânia, GO, 74001-970, Brazil

    Cesar Augusto Sam Tiago Vilanova-Costa, Hellen Karine Paes Porto, Lucas Carlos Gomes Pereira, Bruno Pereira Carvalho & Elisângela de Paula Silveira-Lacerda

  2. Instituto de Ciências Exatas e da Terra, Universidade Federal de Mato Grosso - UFMT, Barra do Garças, MT, 78698-000, Brazil

    Wagner Batista dos Santos

Authors
  1. Cesar Augusto Sam Tiago Vilanova-Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hellen Karine Paes Porto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucas Carlos Gomes Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruno Pereira Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wagner Batista dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisângela de Paula Silveira-Lacerda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cesar Augusto Sam Tiago Vilanova-Costa.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vilanova-Costa, C.A.S.T., Porto, H.K.P., Pereira, L.C.G. et al. MDR1 and Cytochrome P450 Gene-Expression Profiles as Markers of Chemosensitivity in Human Chronic Myelogenous Leukemia Cells Treated with Cisplatin and Ru(III) Metallocomplexes. Biol Trace Elem Res 163, 39–47 (2015). https://doi.org/10.1007/s12011-014-0133-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-014-0133-2

Keywords

Search

Navigation