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Chemo Fog pp 147–156Cite as

Chemo Brain (Chemo Fog) as a Potential Side Effect of Doxorubicin Administration: Role of Cytokine-Induced, Oxidative/Nitrosative Stress in Cognitive Dysfunction

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 678))

Abstract

Doxorubicin (ADRIAMYCIN, RUBEX) is a chemotherapeutic agent that is commonly administered to breast cancer patients in standard chemotherapy regimens. As true of all such therapeutic cytotoxic agents, it can damage normal, noncancerous cells and might affect biochemical processes in a manner that might lead to, or contribute to, chemotherapy-induced cognitive deficits when administered either alone or in combination with other agents.

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References

  1. Silberfarb PM, Philibert D, Levine PM. Psychosocial aspects of neoplastic disease: II. Affective and cognitive effects of chemotherapy in cancer patients. Am J Psychiatry 1980; 137(5):597–601.

    CAS  PubMed  Google Scholar 

  2. Schagen SB, van Dam FS, Muller MJ et al. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85(3):640–650.

    Article  CAS  PubMed  Google Scholar 

  3. Wefel JS, Lenzi R, Theriault RL et al. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 2004; 100(11):2292–2299.

    Article  CAS  PubMed  Google Scholar 

  4. Tchen N, Juffs HG, Downie FP et al. Cognitive function, fatigue and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol 2003; 21(22):4175–4183.

    Article  PubMed  Google Scholar 

  5. Brezden CB, Phillips KA, Abdolell M et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2000; 18(14):2695–2701.

    CAS  PubMed  Google Scholar 

  6. Ahles TA, Saykin AJ, Furstenberg CT et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 2002; 20(2):485–493.

    Article  CAS  PubMed  Google Scholar 

  7. Meyers CA. Neurocognitive dysfunction in cancer patients. Oncology (Williston Park) 2000; 14(1):75–79; discussion 79, 81–72, 85.

    CAS  Google Scholar 

  8. Schagen SB, Hamburger HL, Muller MJ et al. Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. J Neurooncol 2001; 51(2):159–165.

    Article  CAS  PubMed  Google Scholar 

  9. Freeman JR, Broshek DK. Assessing cognitive dysfunction in breast cancer: what are the tools? Clin Breast Cancer 2002; 3(Suppl 3):S91–99.

    Article  PubMed  Google Scholar 

  10. Ahles TA, Saykin A. Cognitive effects of standard-dose chemotherapy in patients with cancer. Cancer Invest 2001; 19(8):812–820.

    Article  CAS  PubMed  Google Scholar 

  11. Ahles TA, Saykin AJ. Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer 2002; 3(Suppl 3):S84–90.

    Article  CAS  PubMed  Google Scholar 

  12. Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 2007; 7(3):192–201.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Correa DD, Ahles TA. Neurocognitive changes in cancer survivors. Cancer J 2008; 14(6):396–400.

    Article  PubMed  Google Scholar 

  14. Castellon SA, Ganz PA, Bower JE et al. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol 2004; 26(7):955–969.

    Article  PubMed  Google Scholar 

  15. Macleod JE, DeLeo JA, Hickey WF et al. Cancer chemotherapy impairs contextual but not cue-specific fear memory. Behav Brain Res 2007; 181(1):168–172.

    Article  CAS  PubMed  Google Scholar 

  16. Silverman DH, Dy CJ, Castellon SA et al. Altered frontocortical, cerebellar and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat 2007; 103(3):303–311.

    Article  CAS  PubMed  Google Scholar 

  17. Wefel JS, Kayl AE, Meyers CA. Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target. Br J Cancer 2004; 90(9):1691–1696.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. van Dam FS, Schagen SB, Muller MJ et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998; 90(3):210–218.

    Article  PubMed  Google Scholar 

  19. Correa DD, Ahles TA. Cognitive adverse effects of chemotherapy in breast cancer patients. Curr Opin Support Palliat Care 2007; 1(1):57–62.

    Article  PubMed  Google Scholar 

  20. Wefel JS, Lenzi R, Theriault R et al. ‘Chemobrain’ in breast carcinoma?: a prologue. Cancer 2004; 101(3):466–475.

    Article  PubMed  Google Scholar 

  21. Cummings J, Anderson L, Willmott N et al. The molecular pharmacology of doxorubicin in vivo. Eur J Cancer 1991; 27(5):532–535.

    Article  CAS  PubMed  Google Scholar 

  22. Fornari FA, Randolph JK, Yalowich JC et al. Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol 1994; 45(4):649–656.

    CAS  PubMed  Google Scholar 

  23. Tanaka M, Yoshida S. Mechanism of the inhibition of calf thymus DNA polymerases alpha and beta by daunomycin and adriamycin. J Biochem 1980; 87(3):911–918.

    CAS  PubMed  Google Scholar 

  24. Chuang RY, Chuang LF. Inhibition of chicken myeloblastosis RNA polymerase II activity by adriamycin. Biochemistry 1979; 18(10):2069–2073.

    Article  CAS  PubMed  Google Scholar 

  25. DeVita VT, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology, 6th. ed: Lippincott, Williams and Wilkins; 2001.

    Google Scholar 

  26. Kalet BT, McBryde MB, Espinosa JM et al. Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism. J Med Chem 2007; 50(18):4493–4500.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Liu LF, Rowe TC, Yang L et al. Cleavage of DNA by mammalian DNA topoisomerase II. J Biol Chem 1983; 258(24):15365–15370.

    CAS  PubMed  Google Scholar 

  28. Chen Y, Daosukho C, Opii WO et al. Redox proteomic identification of oxidized cardiac proteins in adriamycin-treated mice. Free Radic Biol Med 2006; 41(9):1470–1477.

    Article  CAS  PubMed  Google Scholar 

  29. DeAtley SM, Aksenov MY, Aksenova MV et al. Adriamycin-induced changes of creatine kinase activity in vivo and in cardiomyocyte culture. Toxicology 1999; 134(1):51–62.

    Article  CAS  PubMed  Google Scholar 

  30. Jungsuwadee P, Cole MP, Sultana R et al. Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice. Mol Cancer Ther 2006; 5(11):2851–2860.

    Article  CAS  PubMed  Google Scholar 

  31. Minotti G. NADPH-and adriamycin-dependent microsomal release of iron and lipid peroxidation. Arch Biochem Biophys 1990; 277(2):268–276.

    Article  CAS  PubMed  Google Scholar 

  32. Bachur NR, Riggs CE, Green MR et al. Plasma adriamycin and daunorubicin levels by fluorescence and radioimmunoassay. Clin Pharmacol Ther 1977; 21(1):70–77.

    CAS  PubMed  Google Scholar 

  33. Bachur NR, Gee MV, Friedman RD. Nuclear catalyzed antibiotic free radical formation. Cancer Res 1982; 42(3):1078–1081.

    CAS  PubMed  Google Scholar 

  34. Doroshow JH, Davies KJ. Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide and hydroxyl radical. J Biol Chem 1986; 261(7):3068–3074.

    CAS  PubMed  Google Scholar 

  35. Pan SS, Bachur NR. Xanthine oxidase catalyzed reductive cleavage of anthracycline antibiotics and free radical formation. Mol Pharmacol 1980; 17(1):95–99.

    CAS  PubMed  Google Scholar 

  36. Yee SB, Pritsos CA. Comparison of oxygen radical generation from the reductive activation of doxorubicin, streptonigrin and menadione by xanthine oxidase and xanthine dehydrogenase. Arch Biochem Biophys 1997; 347(2):235–241.

    Article  CAS  PubMed  Google Scholar 

  37. Bachur NR, Gordon SL, Gee MV. Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol 1977; 13(5):901–910.

    CAS  PubMed  Google Scholar 

  38. Deres P, Halmosi R, Toth A et al. Prevention of doxorubicin-induced acute cardiotoxicity by an experimental antioxidant compound. J Cardiovasc Pharmacol 2005; 45(1):36–43.

    Article  CAS  PubMed  Google Scholar 

  39. Butterfield DA, Stadtman ER. Protein oxidation processes in the aging brain. Adv Cell Aging Gerontol 1997; 2:161–191.

    Article  CAS  Google Scholar 

  40. Joshi G, Sultana R, Tangpong J et al. Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain. Free Radic Res 2005; 39(11):1147–1154.

    Article  CAS  PubMed  Google Scholar 

  41. Kotamraju S, Konorev EA, Joseph J et al. Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species. J Biol Chem 2000; 275(43):33585–33592.

    Article  CAS  PubMed  Google Scholar 

  42. DeAtley SM, Aksenov MY, Aksenova MV et al. Adriamycin induces protein oxidation in erythrocyte membranes. Pharmacol Toxicol 1998; 83(2):62–68.

    Article  CAS  PubMed  Google Scholar 

  43. Chen Y, Jungsuwadee P, Vore M et al. Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues. Mol Interv 2007; 7(3):147–156.

    Article  CAS  PubMed  Google Scholar 

  44. Ischiropoulos H, Zhu L, Chen J et al. Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch Biochem Biophys 1992; 298(2):431–437.

    Article  CAS  PubMed  Google Scholar 

  45. Berlett BS, Stadtman ER. Protein oxidation in aging, disease and oxidative stress. J Biol Chem 1997; 272(33):20313–20316.

    Article  CAS  PubMed  Google Scholar 

  46. Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 2002; 32(11):1050–1060.

    Article  CAS  PubMed  Google Scholar 

  47. Aluise CD, St Clair D, Vore M et al. In vivo amelioration of adriamycin induced oxidative stress in plasma by gamma-glutamylcysteine ethyl ester (GCEE). Cancer Lett 2009.

    Google Scholar 

  48. Injac R, Boskovic M, Perse M et al. Acute doxorubicin nephrotoxicity in rats with malignant neoplasm can be successfully treated with fullerenol C60(OH)24 via suppression of oxidative stress. Pharmacol Rep 2008; 60(5):742–749.

    CAS  PubMed  Google Scholar 

  49. Qin XJ, He W, Hai CX et al. Protection of multiple antioxidants Chinese herbal medicine on the oxidative stress induced by adriamycin chemotherapy. J Appl Toxicol 2008; 28(3):271–282.

    Article  CAS  PubMed  Google Scholar 

  50. Yeh YC, Liu TJ, Wang LC et al. A standardized extract of Ginkgo biloba suppresses doxorubicin-induced oxidative stress and p53-mediated mitochondrial apoptosis in rat testes. Br J Pharmacol 2009; 156(1):48–61.

    Article  CAS  PubMed  Google Scholar 

  51. Joshi G, Hardas S, Sultana R et al. Glutathione elevation by gamma-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain. J Neurosci Res 2007; 85(3):497–503.

    Article  CAS  PubMed  Google Scholar 

  52. Tangpong J, Cole MP, Sultana R et al. Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain. J Neurochem 2007; 100(1):191–201.

    Article  CAS  PubMed  Google Scholar 

  53. Cardoso S, Santos RX, Carvalho C et al. Doxorubicin increases the susceptibility of brain mitochondria to Ca(2+)-induced permeability transition and oxidative damage. Free Radic Biol Med 2008; 45(10):1395–1402.

    Article  CAS  PubMed  Google Scholar 

  54. Konat GW, Kraszpulski M, James I et al. Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats. Metab Brain Dis 2008; 23(3):325–333.

    Article  CAS  PubMed  Google Scholar 

  55. Romeo HE, Tio DL, Rahman SU et al. The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity. J Neuroimmunol 2001; 115(1–2):91–100.

    Article  CAS  PubMed  Google Scholar 

  56. Watkins LR, Maier SF, Goehler LE. Cytokine-to-brain communication: a review and analysis of alternative mechanisms. Life Sci 1995; 57(11):1011–1026.

    Article  CAS  PubMed  Google Scholar 

  57. Tangpong J, Cole MP, Sultana R et al. Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity. Neurobiol Dis 2006; 23(1):127–139.

    Article  CAS  PubMed  Google Scholar 

  58. Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 2005; 104(4):788–793.

    Article  CAS  PubMed  Google Scholar 

  59. Tonelli LH, Postolache TT, Sternberg EM. Inflammatory genes and neural activity: involvement of immune genes in synaptic function and behavior. Front Biosci 2005; 10:675–680.

    Article  CAS  PubMed  Google Scholar 

  60. Trask PC, Esper P, Riba M et al. Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms and future directions. J Clin Oncol 2000; 18(11):2316–2326.

    CAS  PubMed  Google Scholar 

  61. Bigotte L, Olsson Y. Cytofluorescence localization of adriamycin in the nervous system. III. Distribution of the drug in the brain of normal adult mice after intraventricular and arachnoidal injections. Acta Neuropathol 1982; 58(3):193–202.

    Article  CAS  PubMed  Google Scholar 

  62. Gutierrez EG, Banks WA, Kastin AJ. Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J Neuroimmunol 1993; 47(2):169–176.

    Article  CAS  PubMed  Google Scholar 

  63. Osburg B, Peiser C, Domling D et al. Effect of endotoxin on expression of TNF receptors and transport of TNF-alpha at the blood-brain barrier of the rat. Am J Physiol Endocrinol Metab 2002; 283(5):E899–908.

    CAS  PubMed  Google Scholar 

  64. Usta Y, Ismailoglu UB, Bakkaloglu A et al. Effects of pentoxifylline in adriamycin-induced renal disease in rats. Pediatr Nephrol 2004; 19(8):840–843.

    Article  PubMed  Google Scholar 

  65. Szelenyi J. Cytokines and the central nervous system. Brain Res Bull 2001; 54(4):329–338.

    Article  CAS  PubMed  Google Scholar 

  66. Tangpong J, Sompol P, Vore M et al. Tumor necrosis factor alpha-mediated nitric oxide production enhances manganese superoxide dismutase nitration and mitochondrial dysfunction in primary neurons: an insight into the role of glial cells. Neuroscience 2008; 151(2):622–629.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Heflin LH, Meyerowitz BE, Hall P et al. Cancer as a risk factor for long-term cognitive deficits and dementia. J Natl Cancer Inst 2005; 97(11):854–856.

    Article  PubMed  Google Scholar 

  68. Inagaki M, Yoshikawa E, Matsuoka Y et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer 2007; 109(1):146–156.

    Article  PubMed  Google Scholar 

  69. Stemmer SM, Stears JC, Burton BS et al. White matter changes in patients with breast cancer treated with high-dose chemotherapy and autologous bone marrow support. AJNR Am J Neuroradiol 1994; 15(7):1267–1273.

    CAS  PubMed  Google Scholar 

  70. Mihara M, Erster S, Zaika A et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003; 11(3):577–590.

    Article  CAS  PubMed  Google Scholar 

  71. Phillips KA, Bernhard J. Adjuvant breast cancer treatment and cognitive function: current knowledge and research directions. J Natl Cancer Inst 2003; 95(3):190–197.

    Article  CAS  PubMed  Google Scholar 

  72. Jansen CE, Dodd MJ, Miaskowski CA et al. Preliminary results of a longitudinal study of changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide. Psychooncology 2008; 17(12):1189–1195.

    Article  PubMed  Google Scholar 

  73. Reid-Arndt SA. Breast cancer and “chemobrain”: the consequences of cognitive difficulties following chemotherapy and the potential for recovery. Mo Med 2009; 106(2):127–131.

    PubMed  Google Scholar 

  74. Wang S, Konorev EA, Kotamraju S et al. Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms intermediacy of H(2)O(2)-and p53-dependent pathways. J Biol Chem 2004; 279(24):25535–25543.

    Article  CAS  PubMed  Google Scholar 

  75. American Cancer Society: Global Facts and Figures 2007.

    Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Chemistry, Center of Membrane Sciences and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, 40506-0055, USA

    D. Allan Butterfield

Authors
  1. Christopher D. Aluise
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  2. Rukhsana Sultana
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  3. Jitbangjong Tangpong
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  4. Mary Vore
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  5. Daret St. Clair
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  6. Jeffrey A. Moscow
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  7. D. Allan Butterfield
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Correspondence to D. Allan Butterfield .

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Editors and Affiliations

  1. Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania, USA

    Robert B. Raffa PhD

  2. Department of Pharmacology, Temple University School of Medicine, Phhiladelphia, Pennsylvania, USA

    Ronald J. Tallarida PhD

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Aluise, C.D. et al. (2010). Chemo Brain (Chemo Fog) as a Potential Side Effect of Doxorubicin Administration: Role of Cytokine-Induced, Oxidative/Nitrosative Stress in Cognitive Dysfunction. In: Raffa, R.B., Tallarida, R.J. (eds) Chemo Fog. Advances in Experimental Medicine and Biology, vol 678. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6306-2_19

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