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Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia

The Pharmacogenomics Journal volume 17, pages 274–279 (2017)Cite this article

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Abstract

Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.

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References

  1. Stock W, Douer D, DeAngelo DJ, Arellano M, Advani A, Damon L et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011; 52: 2237–2253.

    Article  CAS  PubMed  Google Scholar 

  2. Chen SH, Pei D, Yang W, Cheng C, Jeha S, Cox NJ et al. Genetic variations in GRIA1 on chromosome 5q33 related to asparaginase hypersensitivity. Clin Pharmacol Ther 2010; 88: 191–196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen SH, Yang W, Fan Y, Stocco G, Crews KR, Yang JJ et al. A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. Leukemia 2011; 25: 66–74.

    Article  PubMed  Google Scholar 

  4. 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  PubMed  PubMed Central  Google Scholar 

  5. Kearney SL, Dahlberg SE, Levy DE, Voss SD, Sallan SE, Silverman LB . Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer 2009; 53: 162–167.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Miao L St, Clair DK . Regulation of superoxide dismutase genes: implications in disease. Free Radic Biol Med 2009; 47: 344–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Huang YS, Su WJ, Huang YH, Chen CY, Chang FY, Lin HC et al. Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol 2007; 47: 128–134.

    Article  CAS  PubMed  Google Scholar 

  8. Lucena MI, Garcia-Martin E, Andrade RJ, Martinez C, Stephens C, Ruiz JD et al. Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology 2010; 52: 303–312.

    Article  CAS  Google Scholar 

  9. Glynn SA, Boersma BJ, Howe TM, Edvardsen H, Geisler SB, Goodman JE et al. A mitochondrial target sequence polymorphism in manganese superoxide dismutase predicts inferior survival in breast cancer patients treated with cyclophosphamide. Clin Cancer Res 2009; 15: 4165–4173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee WM . Drug-induced hepatotoxicity. N Engl J Med 2003; 349: 474–485.

    Article  CAS  PubMed  Google Scholar 

  11. Wilson GJ, Bunpo P, Cundiff JK, Wek RC, Anthony TG . The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment. Am J Physiol Endocrinol Metab 2013; 305: E1124–E1133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Costantini P, Jacotot E, Decaudin D, Kroemer G . Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 2000; 92: 1042–1053.

    Article  CAS  PubMed  Google Scholar 

  13. Choi JY, Nowell SA, Blanco JG, Ambrosone CB . The role of genetic variability in drug metabolism pathways in breast cancer prognosis. Pharmacogenomics 2006; 7: 613–624.

    Article  CAS  PubMed  Google Scholar 

  14. Macmillan-Crow LA, Cruthirds DL . Invited review: manganese superoxide dismutase in disease. Free Radic Res 2001; 34: 325–336.

    Article  CAS  PubMed  Google Scholar 

  15. Zelko IN, Mariani TJ, Folz RJ . Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med 2002; 33: 337–349.

    Article  CAS  PubMed  Google Scholar 

  16. Fridovich I . Superoxide radical and superoxide dismutases. Annu Rev Biochem 1995; 64: 97–112.

    Article  CAS  Google Scholar 

  17. Lebovitz RM, Zhang H, Vogel H, Cartwright J Jr., Dionne L, Lu N et al. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA 1996; 93: 9782–9787.

    Article  CAS  PubMed  Google Scholar 

  18. Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A . Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 1998; 273: 28510–28515.

    Article  CAS  PubMed  Google Scholar 

  19. Ong MM, Wang AS, Leow KY, Khoo YM, Boelsterli UA . Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/-) mice. Free Radic Biol Med 2006; 40: 420–429.

    Article  CAS  PubMed  Google Scholar 

  20. Larosche I, Letteron P, Berson A, Fromenty B, Huang TT, Moreau R et al. Hepatic mitochondrial DNA depletion after an alcohol binge in mice: probable role of peroxynitrite and modulation by manganese superoxide dismutase. J Pharmacol Exp Ther 2010; 332: 886–897.

    Article  CAS  PubMed  Google Scholar 

  21. Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F . The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics 2003; 13: 145–157.

    Article  CAS  PubMed  Google Scholar 

  22. Ambrosone CB, Freudenheim JL, Thompson PA, Bowman E, Vena JE, Marshall JR et al. Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer. Cancer Res 1999; 59: 602–606.

    CAS  PubMed  Google Scholar 

  23. Woodson K, Tangrea JA, Lehman TA, Modali R, Taylor KM, Snyder K et al. Manganese superoxide dismutase (MnSOD) polymorphism, alpha-tocopherol supplementation and prostate cancer risk in the alpha-tocopherol, beta-carotene cancer prevention study (Finland). Cancer Causes Control 2003; 14: 513–518.

    Article  PubMed  Google Scholar 

  24. Hung RJ, Boffetta P, Brennan P, Malaveille C, Gelatti U, Placidi D et al. Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk. Carcinogenesis 2004; 25: 973–978.

    Article  CAS  PubMed  Google Scholar 

  25. Pullarkat ST, Danley K, Bernstein L, Brynes RK, Cozen W . High lifetime incidence of adult acute lymphoblastic leukemia among Hispanics in California. Cancer Epidemiol Biomarkers Prev 2009; 18: 611–615.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bastaki M, Huen K, Manzanillo P, Chande N, Chen C, Balmes JR et al. Genotype-activity relationship for Mn-superoxide dismutase, glutathione peroxidase 1 and catalase in humans. Pharmacogenet Genomics 2006; 16: 279–286.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank the University of Chicago Cancer Research Foundation Women’s Board and Division of Biological Sciences. This work was also supported by the following grants: NIH grants: T32GM007019, UM1 CA186705 and P30 CA14599-36.

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Authors and Affiliations

  1. Department of Pharmacy, USC School of Pharmacy, University of Southern California, Los Angeles,, CA, USA

    H Alachkar

  2. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago,, IL, USA

    N Fulton, G Malnassy, M Mutonga, R A Larson, Y Nakamura & W Stock

  3. Alliance/CALGB Statistical Center, Duke Cancer Institute, Biostatistics,, Durham,, NC, USA

    B Sanford

  4. Division of Hematology, Department of Medicine, The Ohio State University, Columbus,, OH, USA

    C D Bloomfield

  5. Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia, City of Hope Comprehensive Cancer Center, Duarte,, CA, USA

    G Marcucci

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  1. H Alachkar
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Correspondence to W Stock.

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Alachkar, H., Fulton, N., Sanford, B. et al. Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia. Pharmacogenomics J 17, 274–279 (2017). https://doi.org/10.1038/tpj.2016.7

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