METALLOTHIONEIN AND ADRIAMYCIN CARDIOTOXICITY

Summary

Principal Investigator: Y James Kang
Affiliation: University of Louisville
Country: USA
Abstract: DESCRIPTION: (Adapted from the Investigator's Abstract) Cardiotoxicity compromises effective use of adriamycin in cancer chemotherapy. Studies have shown that production of reactive oxygen species during its intracellular metabolism is highly responsible for the toxicity of this drug. Metallothionein (MT), a low molecular weight and cysteine-rich protein, has been shown in recent studies to protect the heart from acute adriamycin toxicity. However, it is important to know whether MT functions effectively in protection against chronic adriamycin cardiotoxicity, a significant clinical problem. Also the mechanism by which MT functions in this cardioprotection in vivo is unknown. Therefore, this study will test the hypothesis that MT protects from chronic adriamycin cardiotoxicity by inhibiting the drug-induced oxidative injury. A unique cardiac MT over expressing transgenic mouse model will be used. The specific aims and experimental approaches are: (1) To test whether elevated MT confers resistance to chronic adriamycin cardiotoxicity, the effects of MT on adriamycin-induced morphological changes in the myocardium, functional alterations in the isolated atrium, and increase in serum creatine phosphokinase activities will be determined in the cardiac MT over expressing transgenic mice and non- transgenic controls. (2) To investigate possible mechanisms by which MT protects the heart from chronic adriamycin toxicity, the subcellular localization, as well as the distribution among cell types, of the elevated cardiac MT, and possible alterations of mineral metabolism associated with the cardiac MT over expression will be measured. Furthermore, effects of MT elevation on adriamycin-induced lipid peroxidation and oxidative DNA lesions, and the reaction of MT with cellular disulfides in the heart will be examined. (3) To determine the specificity of the reaction of MT with GSH disulfide relative to other disulfides, GSH depletion and its effects on the status of cellular disulfides, along with altered adriamycin cardiotoxicity, will be examined. (4) To explore possible strategies for clinical application of MT induction as an approach to decrease adriamycin cardiotoxicity, bismuth with or without hinokitiol will be applied to develop an effectively experimental strategy for cardiac MT induction and protection. This study would provide a substantial base of information for understanding of the role of MT in cardioprotection against chronic adriamycin toxicity, potentially leading to further investigations towards an improved use of adriamycin in cancer chemotherapy.
Funding Period: 1999-04-01 - 2002-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Modulation of cytochrome C oxidase-va is possibly involved in metallothionein protection from doxorubicin cardiotoxicity
    Kevyn E Merten
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 511 South Floyd Street, MDR 530, Louisville, KY 40202, USA
    J Pharmacol Exp Ther 315:1314-9. 2005
  2. ncbi Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts
    Wenke Feng
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Biochem Biophys Res Commun 332:853-8. 2005
  3. ncbi Copper inhibition of hydrogen peroxide-induced hypertrophy in embryonic rat cardiac H9c2 cells
    Yang Zhou
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Exp Biol Med (Maywood) 232:385-9. 2007
  4. pmc Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice
    Youchun Jiang
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    J Exp Med 204:657-66. 2007
  5. ncbi Zinc inhibits doxorubicin-activated calcineurin signal transduction pathway in H9c2 embryonic rat cardiac cells
    Kevyn E Merten
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Exp Biol Med (Maywood) 232:682-9. 2007
  6. ncbi Heavy metal ions in normal physiology, toxic stress, and cytoprotection
    Michael A Lynes
    University of Connecticut, 91 N Eagleville Road, Storrs, CT 06269, USA
    Ann N Y Acad Sci 1113:159-72. 2007
  7. pmc Metallothionein rescues hypoxia-inducible factor-1 transcriptional activity in cardiomyocytes under diabetic conditions
    Wenke Feng
    Department of Medicine, University of Louisville School of Medicine, 511 S Floyd Street, MDR532, Louisville, KY 40202, USA
    Biochem Biophys Res Commun 360:286-9. 2007
  8. ncbi Antioxidant defense against anthracycline cardiotoxicity by metallothionein
    Y James Kang
    University of Louisville School of Medicine, 511 S Floyd St, MDR530, Louisville, KY 40202, USA
    Cardiovasc Toxicol 7:95-100. 2007
  9. pmc Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart
    Y James Kang
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    J Nutr Biochem 18:714-8. 2007
  10. pmc Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size
    Yang Zhou
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
    J Mol Cell Cardiol 45:106-17. 2008

Scientific Experts

  • Y James Kang
  • Lu Cai
  • ZHANXIANG contact ZHOU
  • M George Cherian
  • Vishnudutt Purohit
  • Wenke Feng
  • Youchun Jiang
  • Kevyn E Merten
  • Yang Zhou
  • Jack T Saari
  • Jian Cai
  • Huiqi Xie
  • Michael A Lynes
  • Frederick W Benz
  • William M Pierce
  • Lipeng Wang
  • Ye Song
  • Wanli Xue
  • Fei Ye
  • Walter Rodriguez
  • Stefano L Sensi
  • Corey Reynolds
  • Chang Xiao
  • Yuehui Wang
  • John W Eaton
  • Lawrence E Hightower
  • Suresh C Tyagi
  • George A Perdrizet
  • Jon B Klein
  • Yibo Du
  • Jianxun Wang
  • Li Zhang
  • William Pierce
  • Renty B Franklin
  • Gavin E Arteel
  • Yan Li
  • Wolfgang Maret

Detail Information

Publications24

  1. ncbi Modulation of cytochrome C oxidase-va is possibly involved in metallothionein protection from doxorubicin cardiotoxicity
    Kevyn E Merten
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 511 South Floyd Street, MDR 530, Louisville, KY 40202, USA
    J Pharmacol Exp Ther 315:1314-9. 2005
    ..Because CCO-Va is a critical component in the mitochondrial electron transport chain, the results suggest that the cardioprotective effect of MT may be related to an increased expression or a differential modification of CCO-Va...
  2. ncbi Metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts
    Wenke Feng
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Biochem Biophys Res Commun 332:853-8. 2005
    ..The m-aconitase, not the cytosolic aconitase (c-aconitase), was co-immunoprecipitated with MT. This study demonstrates that MT transfers zinc to m-aconitase through a direct interaction...
  3. ncbi Copper inhibition of hydrogen peroxide-induced hypertrophy in embryonic rat cardiac H9c2 cells
    Yang Zhou
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Exp Biol Med (Maywood) 232:385-9. 2007
    ..The results thus demonstrated that VEGF is critically involved in copper inhibition of cell hypertrophy induced by hydrogen peroxide in the H9c2 cells...
  4. pmc Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice
    Youchun Jiang
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    J Exp Med 204:657-66. 2007
    ..Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1alpha activation of VEGF expression and angiogenesis...
  5. ncbi Zinc inhibits doxorubicin-activated calcineurin signal transduction pathway in H9c2 embryonic rat cardiac cells
    Kevyn E Merten
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Exp Biol Med (Maywood) 232:682-9. 2007
    ..It had been shown previously that calcineurin is also not necessary for DOX-induced H9c2 cell hypertrophy.)...
  6. ncbi Heavy metal ions in normal physiology, toxic stress, and cytoprotection
    Michael A Lynes
    University of Connecticut, 91 N Eagleville Road, Storrs, CT 06269, USA
    Ann N Y Acad Sci 1113:159-72. 2007
    ..In this minireview, we will consider both the biological responses to stressful levels of heavy metal cations, and experimental and clinical manipulations of these cations as a means to improve human health parameters...
  7. pmc Metallothionein rescues hypoxia-inducible factor-1 transcriptional activity in cardiomyocytes under diabetic conditions
    Wenke Feng
    Department of Medicine, University of Louisville School of Medicine, 511 S Floyd Street, MDR532, Louisville, KY 40202, USA
    Biochem Biophys Res Commun 360:286-9. 2007
    ..The addition of MT into the cultures of H9c2 cells relieved the HG suppression of hypoxia-induced luciferase activity. This study indicates that MT can rescue HIF-1 transcriptional activity in cardiomyocytes under diabetic conditions...
  8. ncbi Antioxidant defense against anthracycline cardiotoxicity by metallothionein
    Y James Kang
    University of Louisville School of Medicine, 511 S Floyd St, MDR530, Louisville, KY 40202, USA
    Cardiovasc Toxicol 7:95-100. 2007
    ..In addition, MT posttranslationally modulates critical proteins involved in mitochondrial respiration and energy metabolism. All of these processes constitute the mechanisms by which MT protects from anthracycline cardiotoxicity...
  9. pmc Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart
    Y James Kang
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    J Nutr Biochem 18:714-8. 2007
    ..These results suggest that elevation in zinc but not in copper in the heart may be involved in the MT inhibition of copper deficiency-induced cardiac hypertrophy...
  10. pmc Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size
    Yang Zhou
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
    J Mol Cell Cardiol 45:106-17. 2008
    ..2 microg/ml reversed cell hypertrophy as the same as copper did. This study demonstrates that both copper and VEGF reduce the size of hypertrophied cardiomyocytes, and copper regression of cardiac hypertrophy is VEGF-dependent...
  11. pmc Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium
    Vishnudutt Purohit
    Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5635 Fishers Lane, Room 2035, MSC 9304, Bethesda, MD 20892 9304, USA
    Alcohol 42:349-61. 2008
    ..Thus reducing the number of intestinal Gram-negative bacteria and preserving intestinal permeability to endotoxin may attenuate alcoholic liver and other organ injuries...
  12. pmc Copper regulation of hypoxia-inducible factor-1 activity
    Wenke Feng
    Departments of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Mol Pharmacol 75:174-82. 2009
    ..This study thus defines that copper is required for HIF-1 activation through the regulation of HIF-1alpha binding to the HRE and the formation of the HIF-1 transcriptional complex...
  13. ncbi Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy
    Lu Cai
    Department of Medicine, The University of Louisville, Louisville, Kentucky, USA
    J Am Coll Cardiol 48:1688-97. 2006
    ..We aimed to test whether attenuation of early-phase cardiac cell death can prevent diabetic cardiomyopathy...
  14. ncbi Metallothionein redox cycle and function
    Y James Kang
    Department of Medicine, University of Louisville School of Medicine, 511 S Floyd Street, MDR 530, Louisville, KY 40202, USA
    Exp Biol Med (Maywood) 231:1459-67. 2006
    ..This MT redox cycle may play a crucial role in MT biologic function. It may link to the homeostasis of essential metals, detoxification of toxic metals and protection against oxidative stress...
  15. ncbi Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy
    Lu Cai
    Department of Medicine, University of Louisville School of Medicine, 511 South Floyd St, MDR 533, Louisville, KY 40202, USA
    Diabetes 54:1829-37. 2005
    ..These results thus suggest that metallothionein prevention of diabetic cardiomyopathy is mediated, at least in part, by suppression of superoxide generation and associated nitrosative damage...
  16. pmc Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress
    Zhanxiang Zhou
    University of Louisville School of Medicine, Department of Medicine, 511 South Floyd St, MDR 529, Louisville, KY 40292, USA
    Am J Pathol 166:1681-90. 2005
    ..In conclusion, zinc supplementation prevents alcoholic liver injury in an metallothionein-independent manner by inhibiting the generation of reactive oxygen species (P450 2E1) and enhancing the activity of antioxidant pathways...
  17. pmc Cardiac metallothionein synthesis in streptozotocin-induced diabetic mice, and its protection against diabetes-induced cardiac injury
    Ye Song
    Department of Medicine, University of Louisville, Louisville, KY, USA
    Am J Pathol 167:17-26. 2005
    ..Overexpressing cardiac MT significantly protects the heart from diabetes-induced injury...
  18. pmc Alcohol-induced myocardial fibrosis in metallothionein-null mice: prevention by zinc supplementation
    Lipeng Wang
    Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Am J Pathol 167:337-44. 2005
    ....
  19. ncbi Zinc prevention and treatment of alcoholic liver disease
    Y James Kang
    Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
    Mol Aspects Med 26:391-404. 2005
    ..Zn has a high potential to be developed as an effective agent in the prevention and treatment of ALD...
  20. ncbi Metallothionein disulfides are present in metallothionein-overexpressing transgenic mouse heart and increase under conditions of oxidative stress
    Wenke Feng
    Department of Medicine, University of Louisville, KY 40292, USA
    J Biol Chem 281:681-7. 2006
    ..Additional zinc release from MT under oxidative stress conditions is accompanied by more MT disulfide bond formation...
  21. ncbi Metallothionein and liver cell regeneration
    M George Cherian
    Department of Pathology, University of Western Ontario, London, Ontario N6A 5C1, Canada
    Exp Biol Med (Maywood) 231:138-44. 2006
    ..Several studies have suggested a defective liver regeneration after an injury in MT-knockout mice. There is cumulative evidence that indicates an essential role for MT in liver cell regeneration...
  22. ncbi Cardiac hypertrophy: a risk factor for QT-prolongation and cardiac sudden death
    Y James Kang
    Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA
    Toxicol Pathol 34:58-66. 2006
    ..The adaptation of new approaches such as functional genomics and proteomics will further advance our knowledge of heart hypertrophy...
  23. ncbi Calcineurin activation is not necessary for Doxorubicin-induced hypertrophy in H9c2 embryonic rat cardiac cells: involvement of the phosphoinositide 3-kinase-Akt pathway
    Kevyn E Merten
    Department of Medicine, University of Louisville School of Medicine, 511 South Floyd Street, MDR 530, Louisville, KY 40202, USA
    J Pharmacol Exp Ther 319:934-40. 2006
    ..Rather, the PI3K-Akt signaling pathway seems to be more critically involved in DOX-induced hypertrophy...
  24. ncbi Role of copper in angiogenesis and its medicinal implications
    Huiqi Xie
    Division of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P R China
    Curr Med Chem 16:1304-14. 2009
    ..In this context, a development of diagnosis for copper metabolic changes as well as a tissue-specific copper manipulation would greatly benefit patients with an implication of copper manipulation therapy...