Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia

A Corrigendum to this article was published on 13 December 2016

Abstract

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8–12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Kremer LC, Caron HN . Anthracycline cardiotoxicity in children. N Engl J Med 2004; 351: 120–121.

    Article  CAS  Google Scholar 

  2. Shan K, Lincoff AM, Young JB . Anthracycline-induced cardiotoxicity. Ann Inter Med 1996; 125: 47–58.

    Article  CAS  Google Scholar 

  3. Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 2005; 23: 2629–2636.

    Article  CAS  Google Scholar 

  4. Lipshultz SE, Alvarez JA, Scully RE . Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94: 525–533.

    Article  CAS  Google Scholar 

  5. Wojtacki J, Lewicka-Nowak E, Lesniewski-Kmak K . Anthracycline-induced cardiotoxicity: clinical course, risk factors, pathogenesis, detection and prevention—review of the literature. Med Sci Monit 2000; 6: 411–420.

    CAS  PubMed  Google Scholar 

  6. Mushlin PS, Cusack BJ, Boucek RJ Jr., Andrejuk T, Li X, Olson RD . Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br J Pharmacol 1993; 110: 975–982.

    Article  CAS  Google Scholar 

  7. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 2011; 21: 440–446.

    Article  CAS  Google Scholar 

  8. Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A et al. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 2005; 112: 3754–3762.

    Article  CAS  Google Scholar 

  9. Semsei AF, Erdelyi DJ, Ungvari I, Csagoly E, Hegyi MZ, Kiszel PS et al. ABCC1 polymorphisms in anthracycline-induced cardiotoxicity in childhood acute lymphoblastic leukaemia. Cell Biol Int 2012; 36: 79–86.

    Article  CAS  Google Scholar 

  10. Armenian SH, Ding Y, Mills G, Sun C, Venkataraman K, Wong FL et al. Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. Br J Haematol 2013; 163: 205–213.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Blanco JG, Leisenring WM, Gonzalez-Covarrubias VM, Kawashima TI, Davies SM, Relling MV et al. Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer. Cancer 2008; 112: 2789–2795.

    Article  Google Scholar 

  12. Rajic V, Aplenc R, Debeljak M, Prestor VV, Karas-Kuzelicki N, Mlinaric-Rascan I et al. Influence of the polymorphism in candidate genes on late cardiac damage in patients treated due to acute leukemia in childhood. Leuk Lymphoma 2009; 50: 1693–1698.

    Article  CAS  Google Scholar 

  13. Visscher H, Ross CJ, Rassekh SR, Barhdadi A, Dube MP, Al-Saloos H et al. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J Clin Oncol 2012; 30: 1422–1428.

    Article  Google Scholar 

  14. Wang X, Liu W, Sun CL, Armenian SH, Hakonarson H, Hageman L et al. Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group. J Clin Oncol 2014; 32: 647–653.

    Article  CAS  Google Scholar 

  15. Lipshultz SE, Lipsitz SR, Kutok JL, Miller TL, Colan SD, Neuberg DS et al. Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer 2013; 119: 3555–3562.

    Article  CAS  Google Scholar 

  16. Moghrabi A, Levy DE, Asselin B, Barr R, Clavell L, Hurwitz C et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 2007; 109: 896–904.

    Article  CAS  Google Scholar 

  17. Vrooman LM, Stevenson KE, Supko JG, O'Brien J, Dahlberg SE, Asselin BL et al. Postinduction dexamethasone and individualized dosing of Escherichia coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 2013; 31: 1202–1210.

    Article  CAS  Google Scholar 

  18. Silverman LB, Stevenson KE, O'Brien JE, Asselin BL, Barr RD, Clavell L et al. Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000). Leukemia 2010; 24: 320–334.

    Article  CAS  Google Scholar 

  19. Rousseau J, Gagne V, Labuda M, Beaubois C, Sinnett D, Laverdiere C et al. ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia. Blood 2011; 118: 5883–5890.

    Article  CAS  Google Scholar 

  20. Ben Tanfous M, Sharif-Askari B, Ceppi F, Laaribi H, Gagne V, Rousseau J et al. Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia. Clin Cancer Res 2014; 21: 329–334.

    Article  Google Scholar 

  21. Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB, Miller TL et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 2010; 11: 950–961.

    Article  CAS  Google Scholar 

  22. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–367.

    Article  CAS  Google Scholar 

  23. Ansari M, Sauty G, Labuda M, Gagne V, Laverdiere C, Moghrabi A et al. Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood 2009; 114: 1383–1386.

    Article  CAS  Google Scholar 

  24. Ansari M, Sauty G, Labuda M, Gagne V, Rousseau J, Moghrabi A et al. Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia. Pharmacogenomics J 2012; 12: 386–394.

    Article  CAS  Google Scholar 

  25. Krajinovic M, Labuda D, Mathonnet G, Labuda M, Moghrabi A, Champagne J et al. Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to treatment of childhood acute lymphoblastic leukemia. Clin Cancer Res 2002; 8: 802–810.

    CAS  PubMed  Google Scholar 

  26. Marcoux S, Robaey P, Gahier A, Labuda M, Rousseau J, Sinnett D et al. Role of NOS3 DNA variants in externalizing behavioral problems observed in childhood leukemia survivors. J Pediatric Hematol Oncol 2013; 35: e157–e162.

    Article  CAS  Google Scholar 

  27. Storey JD, Taylor JE, Siegmund D . Strong control, conservative point estimation and simultaneous conservative consistency of false discovery rates: a unified approach. J R Stat Soc B (Stat Methodol) 2004; 66: 187–205.

    Article  Google Scholar 

  28. Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004; 351: 145–153.

    Article  CAS  Google Scholar 

  29. Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J . Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 2000; 97: 2832–2835.

    Article  CAS  Google Scholar 

  30. Polanski AK, Ebner A, Ebner B, Hofmann A, Steinbronn N, Brandt A et al. Dexrazoxane prevents the development of the impaired cardiac phenotype in caveolin-1-disrupted mice. J Cardiovasc Pharmacol 2013; 61: 545–552.

    Article  CAS  Google Scholar 

  31. Neilan TG, Blake SL, Ichinose F, Raher MJ, Buys ES, Jassal DS et al. Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation 2007; 116: 506–514.

    Article  CAS  Google Scholar 

  32. Deng S, Kruger A, Schmidt A, Metzger A, Yan T, Godtel-Armbrust U et al. Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Naunyn Schmiedebergs Arch Pharmacol 2009; 380: 25–34.

    Article  CAS  Google Scholar 

  33. Mungrue IN, Husain M, Stewart DJ . The role of NOS in heart failure: lessons from murine genetic models. Heart Fail Rev 2002; 7: 407–422.

    Article  CAS  Google Scholar 

  34. Brunner F, Andrew P, Wolkart G, Zechner R, Mayer B . Myocardial contractile function and heart rate in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Circulation 2001; 104: 3097–3102.

    Article  CAS  Google Scholar 

  35. Chand S, Chue CD, Edwards NC, Hodson J, Simmonds MJ, Hamilton A et al. Endothelial nitric oxide synthase single nucleotide polymorphism and left ventricular function in early chronic kidney disease. PLoS One 2015; 10: e0116160.

    Article  Google Scholar 

  36. Visscher H, Ross CJ, Rassekh SR, Sandor GS, Caron HN, van Dalen EC et al. Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr Blood Cancer 2013; 60: 1375–1381.

    Article  CAS  Google Scholar 

  37. Lal S, Mahajan A, Chen WN, Chowbay B . Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr Drug Metab 2010; 11: 115–128.

    Article  CAS  Google Scholar 

  38. Yoshida M, Suzuki T, Komiya T, Hatashita E, Nishio K, Kazuhiko N et al. Induction of MRP5 and SMRP mRNA by adriamycin exposure and its overexpression in human lung cancer cells resistant to adriamycin. Int J Cancer 2001; 94: 432–437.

    Article  CAS  Google Scholar 

  39. Luo JQ, Wen JG, Zhou HH, Chen XP, Zhang W . Endothelial nitric oxide synthase gene G894T polymorphism and myocardial infarction: a meta-analysis of 34 studies involving 21,068 subjects. PLoS One 2014; 9: e87196.

    Article  Google Scholar 

  40. Fogli S, Nieri P, Breschi MC . The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. FASEB J 2004; 18: 664–675.

    Article  CAS  Google Scholar 

  41. Dazert P, Meissner K, Vogelgesang S, Heydrich B, Eckel L, Bohm M et al. Expression and localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart. Am J Pathol 2003; 163: 1567–1577.

    Article  CAS  Google Scholar 

  42. Jedlitschky G, Burchell B, Keppler D . The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J Biol Chem 2000; 275: 30069–30074.

    Article  CAS  Google Scholar 

  43. Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP . Molecular mechanism of cGMP-mediated smooth muscle relaxation. J Cell Physiol 2000; 184: 409–420.

    Article  CAS  Google Scholar 

  44. Flesch M, Kilter H, Cremers B, Lenz O, Sudkamp M, Kuhn-Regnier F et al. Acute effects of nitric oxide and cyclic GMP on human myocardial contractility. J Pharmacol Exp Ther 1997; 281: 1340–1349.

    CAS  PubMed  Google Scholar 

  45. Wollert KC, Fiedler B, Gambaryan S, Smolenski A, Heineke J, Butt E et al. Gene transfer of cGMP-dependent protein kinase I enhances the antihypertrophic effects of nitric oxide in cardiomyocytes. Hypertension 2002; 39: 87–92.

    Article  CAS  Google Scholar 

  46. Wang Z, Wang J, Chong SS, Lee CGL . Mining potential functionally significant polymorphisms at the ATP-binding- cassette transporter genes. Curr Pharmacogenomics Personal Med 2009; 7: 40–58.

    Article  Google Scholar 

  47. Di Leo A, Desmedt C, Bartlett JM, Piette F, Ejlertsen B, Pritchard KI et al. HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol 2011; 12: 1134–1142.

    Article  CAS  Google Scholar 

  48. Khiati S, Dalla Rosa I, Sourbier C, Ma X, Rao VA, Neckers LM et al. Mitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin Cancer Res 2014; 20: 4873–4881.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all patients and their parents who consented to participate in genetics studies related to leukemia. Canadian Institutes of Health Research supported this study. We thank Kristen Stevenson for retrieving the DFCI data. Dana-Farber Cancer Institute ALL treatment protocols are supported by the National Cancer Institute/NIH grant 5 P01CA068484.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Krajinovic.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Krajinovic, M., Elbared, J., Drouin, S. et al. Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia. Pharmacogenomics J 16, 530–535 (2016). https://doi.org/10.1038/tpj.2015.63

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.63

This article is cited by

Search

Quick links