Metallothionein as a scavenger of free radicals – new cardioprotective therapeutic agent or initiator of tumor chemoresistance?

Current Drug Targets

Volumn 17, Issue 12, 2016, Pages 1438-1451

  Heger, Zbynek ^a,b   Rodrigo, Miguel Angel Merlos ^a,b   Krizkova, Sona ^a,b   Ruttkay Nedecky, Branislav ^a   Zalewska, Marta ^c   Del Pozo, Elena Maria Planells ^d   Pelfrene, Aurelie ^e   Pourrut, Bertrand ^e   Stiborova, Marie ^f   Eckschlager, Tomas ^g   Emri, Gabriella ^h   Kizek, Rene ^a,b   Adam, Vojtech ^a,b  

^a BRNO UNIVERSITY OF TECHNOLOGY   (Czech Republic)

^b MENDEL UNIVERSITY IN BRNO   (Czech Republic)

^c WROCLAW MEDICAL UNIVERSITY   (Poland)

^d UNIVERSITY OF GRANADA   (Spain)

^e Mines Douai   (France)

^f CHARLES UNIVERSITY   (Czech Republic)

^g UNIVERSITY HOSPITAL MOTOL   (Czech Republic)

^h UNIVERSITY OF DEBRECEN   (Hungary)

Author keywords

Anthracyclines; Cardioprotection; Cellular oxidative stress; Chemoresistance; Doxorubicin; Free radicals; Metallothionein

Indexed keywords

ANTHRACYCLINE; ASCORBIC ACID; COPPER; HYDROGEN PEROXIDE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MELATONIN; METALLOTHIONEIN; METALLOTHIONEIN I; METALLOTHIONEIN II; METALLOTHIONEIN III; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; RAZOXANE; REACTIVE OXYGEN METABOLITE; RETINOL; STAT3 PROTEIN; ZINC; ANTINEOPLASTIC ANTIBIOTIC; CARDIOTONIC AGENT; FREE RADICAL; SCAVENGER;

ANTIOXIDANT ACTIVITY; CALCIUM HOMEOSTASIS; CARDIOMYOPATHY; CARDIOTOXICITY; CELL DAMAGE; CHELATION; CYTOTOXICITY; DETOXIFICATION; HEART PROTECTION; HUMAN; LIPID PEROXIDATION; NONHUMAN; OXIDATIVE STRESS; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CARDIOMYOPATHIES; CHEMICALLY INDUCED; DRUG EFFECTS; DRUG RESISTANCE; HEART FAILURE; METABOLISM; NEOPLASMS; PATHOLOGY;

ANIMALS; ANTHRACYCLINES; ANTIBIOTICS, ANTINEOPLASTIC; CARDIOMYOPATHIES; CARDIOTONIC AGENTS; DRUG RESISTANCE, NEOPLASM; FREE RADICAL SCAVENGERS; FREE RADICALS; HEART FAILURE; HUMANS; METALLOTHIONEIN; NEOPLASMS; OXIDATIVE STRESS;

EID: 84983782451     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/1389450116666151001113304     Document Type: Review

References (219)

1. Heger Z, Cernei N, Kudr J, et al. A novel insight into the cardiotoxicity of antineoplastic drug doxorubicin. Int J Mol Sci 2013; 14(11): 21629-46.
2. Vejpongsa P, Yeh ETH. Prevention of anthracycline-induced cardiotoxicity. J Am Coll Cardiol 2014; 64(9): 938-45.
3. Arafa MH, Mohammad NS, Atteia HH, Abd-Elaziz HR. Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats. J Physiol Biochem 2014; 70(3): 701-11.
4. Prochazka P, Libra A, Zemanova Z, et al. Mechanisms of ellipticine-mediated resistance in UKF-NB-4 neuroblastoma cells. Cancer Sci 2012; 103(2): 334-41.
5. Maccarinelli F, Gammella E, Asperti M, et al. Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity. J Mol Med 2014; 92(8): 859-69.
6. Yap XL, Tan HY, Huang JX, et al. Over-expression of metallothionein predicts chemoresistance in breast cancer. J Pathol 2009; 217(4): 563-70.
7. Choi CH, Kim HS, Kweon OS, et al. Reactive oxygen speciesspecific mechanisms of drug resistance in paraquat-resistant acute myelogenous leukemia sublines. Mol Cells 2000; 10(1): 38-46.
8. Habel N, Hamidouche Z, Girault I, et al. Zinc chelation: a metallothionein 2A's mechanism of action involved in osteosarcoma cell death and chemotherapy resistance. Cell Death Dis 2013; 4: 1-10.
9. Harrison IP, Selemidis S. Understanding the biology of reactive oxygen species and their link to cancer: NADPH oxidases as novel pharmacological targets. Clin Exp Pharmacol Physiol 2014; 41(8): 533-42.
10. Liou GY, Storz P. Reactive oxygen species in cancer. Free Radical Res 2010; 44(5): 479-96.
11. Yang Y, Karakhanova S, Werner J, Bazhin AV. Reactive oxygen species in cancer biology and anticancer therapy. Curr Med Chem 2013; 20(30): 3677-92.
12. Sullivan LB, Martinez-Garcia E, Nguyen H, et al. The protooncometabolite fumarate binds glutathione to amplify ROSdependent signaling. Mol Cell 2013; 51(2): 236-48.
13. Mishra B, Sangwan RS, Mishra S, Jadaun JS, Sabir F, Sangwan NS. Effect of cadmium stress on inductive enzymatic and nonenzymatic responses of ROS and sugar metabolism in multiple shoot cultures of Ashwagandha (Withania somnifera Dunal). Protoplasma 2014; 251(5): 1031-45.
14. Molina N, Morandi AC, Bolin AP, Otton R. Comparative effect of fucoxanthin and vitamin C on oxidative and functional parameters of human lymphocytes. Int Immunopharmacol 2014; 22(1): 41-50.
15. Venditti P, Napolitano G, Barone D, Di Meo S. Vitamin E supplementation modifies adaptive responses to training in rat skeletal muscle. Free Radical Res 2014; 48(10): 1179-89.
16. Seto NOL, Hayashi S, Tener GM. Overexpression of Cu-Zn superoxide-dismutase in Drosophila does not affect life-span. Proc Natl Acad Sci USA 1990; 87(11): 4270-4.
17. Groitl B, Jakob U. Thiol-based redox switches. BBA-Proteins Proteomics 2014; 1844(8): 1335-43.
18. Storz P. Reactive oxygen species in tumor progression. Front Biosci 2005; 10: 1881-96.
19. Chiarugi P, Fiaschi T. Redox signalling in anchorage-dependent cell growth. Cell Signal 2007; 19(4): 672-82.
20. Rhee SG, Bae YS, Lee SR, Kwon J. Hydrogen peroxide: a key messenger that modulates protein phosphorylation through cysteine oxidation. Sci STKE 2000; 2000(53): 1-2.
21. Harris IS, Blaser H, Moreno J, et al. PTPN12 promotes resistance to oxidative stress and supports tumorigenesis by regulating FOXO signaling. Oncogene 2014; 33(8): 1047-54.
22. Satoh K, Godo S, Saito H, Enkhjargal B, Shimokawa H. Dual roles of vascular-derived reactive oxygen species-With a special reference to hydrogen peroxide and cyclophilin A. J Mol Cell Cardiol 2014; 73: 50-6.
23. Kohler AC, Sag CM, Maier LS. Reactive oxygen species and excitation-contraction coupling in the context of cardiac pathology. J Mol Cell Cardiol 2014; 73: 92-102.
24. Luczak ED, Anderson ME. CaMKII oxidative activation and the pathogenesis of cardiac disease. J Mol Cell Cardiol 2014; 73: 112-6.
25. Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat-heart. Cancer Res 1983; 43(2): 460-72.
26. Gems D, Partridge L. Stress-response hormesis and aging: "That which Does Not Kill Us Makes Us Stronger". Cell Metab 2008; 7(3): 200-3.
27. Schmeisser S, Schmeisser K, Weimer S, et al. Mitochondrial hormesis links low-dose arsenite exposure to lifespan extension. Aging Cell 2013; 12(3): 508-17.
28. Pearce OMT, Laubli H, Verhagen A, et al. Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. Proc Natl Acad Sci USA 2014; 111(16): 5998-6003.
29. Shore DE, Ruvkun G. A cytoprotective perspective on longevity regulation. Trends Cell Biol 2013; 23(9): 409-20.
30. Takemura G, Fujiwara H. Doxorubicin-induccd cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis 2007; 49(5): 330-52.
31. Davies KJA, Doroshow JH. Redox cycling of anthracyclines by cardiac mitochondria.1. anthracycline radical formation by NADH dehydrogenase. J Biol Chem 1986; 261(7): 3060-7.
32. Berlin V, Haseltine WA. Reduction of adriamycin to a semiquinone-free radical by NADPH cytochrome-P-450 reductase produces DNA cleavage in a reaction mediated by molecularoxygen J Biol Chem 1981; 256(10): 4747-56.
33. VasquezVivar J, Martasek P, Hogg N, Masters BSS, Pritchard KA, Kalyanaraman B. Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry 1997; 36(38): 11293-7.
34. Bachur NR, Gordon SL, Gee MV, Kon H. NADPH cytochrome-P-450 reductase activation of quinone anti-cancer agents to freeradicals. Proc Natl Acad Sci USA 1979; 76(2): 954-7.
35. Schimmel KJM, Richel DJ, van den Brink RBA, Guchelaar HJ. Cancer Treat. Rev. Cancer Treat Rev 2004; 30(2): 181-91.
36. Sabuncuoglu S. Antiapoptotic effect of aminoguanidine on doxorubicin-induced apoptosis. Mol Cell Biochem 2014; 394(1-2): 129-35.
37. Beyer AM, Durand MJ, Hockenberry J, Gamblin TC, Phillips SA, Gutterman DD. An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles. Am J Physiol-Heart Circul Physiol 2014; 307(11): H1587-H93.
38. Pall ML. The NO/ONOO-Cycle as the Central Cause of Heart Failure. Int J Mol Sci 2013; 14(11): 22274-330.
39. Myers CE, McGuire WP, Liss RH, Ifrim I, Grotzinger K, Young RC. Adriamycin -role of lipid peroxidation in cardiac toxicity and tumor response. Science 1977; 197(4299): 165-7.
40. Mimnaugh EG, Siddik ZH, Drew R, Sikic BI, Gram TE. Effects of alpha-tocopherol on the toxicity, disposition, and metabolism of adriamycin in mice Toxicol Appl Pharmacol 1979; 49(1): 119-26.
41. Chatterjee K, Zhang JQ, Honbo N, Karliner JS. Doxorubicin Cardiomyopathy. Cardiology 2010; 115(2): 155-62.
42. Hermansen K, Wassermann K. The effect of vitamin-E and selenium on doxorubicin (adriamycin) induced delayed toxicity in mice. Acta Pharmacol Toxicol 1986; 58(1): 31-7.
43. Vanvleet JF, Ferrans VJ, Weirich WE. Cardiac disease induced by chronic adriamycin administration in dogs and an evaluation of vitamin-E and selenium as cardioprotectants Am J Pathol 1980; 99(1): 13-41.
44. Shimpo K, Nagatsu T, Yamada K, Sato T, Niimi H, Shamoto M, et al. Ascorbic-acid and adriamycin toxicity. Am J Clin Nutr 1991; 54(6): S1298-S301.
45. Yoda Y, Nakazawa M, Abe T, Kawakami Z. Prevention of doxorubicin myocardial toxicity in mice by reduced glutathione. Cancer Res 1986; 46(5): 2551-6.
46. Siveskiiliskovic N, Hill M, Chow DA, Singal PK. Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor effect. Circulation 1995; 91(1): 10-5.
47. Siveskiiliskovic N, Kaul N, Singal PK. Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation 1994; 89(6): 2829-35.
48. El-Demerdash E, Ali AA, Sayed-Ahmed MM, Osman AMM. New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol 2003; 52(5): 411-6.
49. Matsui H, Morishima I, Numaguchi Y, Toki Y, Okumura K, Hayakawa T. Protective effects of carvedilol against doxorubicininduced cardiomyopathy in rats. Life Sci 1999; 65(12): 1265-74.
50. Feuerstein G, Yue TL, Ma XL, Ruffolo RR. Novel mechanisms in the treatment of heart failure: Inhibition of oxygen radicals and apoptosis by carvedilol. Prog Cardiovasc Dis 1998; 41(1): 17-24.
51. Oliveira PJ, Bjork JA, Santos MS, et al. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 2004 Oct; 200(2): 159-68.
52. Fazio S, Palmieri EA, Ferravante B, Bone F, Biondi B, Sacca L. Doxorubicin-induced cardiomyopathy treated with carvedilol. Clin Cardiol 1998; 21(10): 777-9.
53. Santos DL, Moreno AJM, Leino RL, Froberg MK, Wallace KB. Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Toxicol Appl Pharmacol 2002; 185(3): 218-27.
54. Seifert CF, Nesser ME, Thompson DF. Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother 1994; 28(9): 1063-72.
55. Vile GF, Winterbourn CC. DL-N,N'-dicarboxamidomethyl-N,N'-dicarboxymethyl-1,2-diaminopropane (ICRF-198) and D-1,2-bis(3,5-dioxopiperazine-1-yl)propane (ICRF-187) inhibition of Fe-3+ reduction, lipid-peroxidation, and caatpase inactivation in heart microsomes exposed to adriamycin. Cancer Res 1990; 50(8): 2307-10.
56. Herman EH, Ferrans VJ. Reduction of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane(ICRF-187). Cancer Res 1981; 41(9): 3436-40.
57. Vonhoff DD, Howser D, Lewis BJ, Holcenberg J, Weiss RB, Young RC. Phase-1 study of ICRF-187 using a daily for 3 days schedule. CancTreat Rep 1981; 65(3-4): 249-52.
58. Kimura T, Fujita I, Itoh N, et al. Metallothionein acts as a cytoprotectant against doxorubicin toxicity. J Pharmacol Exp Ther 2000; 292(1): 299-302.
59. Kang YJ, Chen Y, Yu AD, VossMcCowan M, Epstein PN. Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity. J Clin Invest 1997; 100(6): 1501-6.
60. Wu HY, Kang YJ. Inhibition of buthionine sulfoximine-enhanced doxorubicin toxicity in metallothionein overexpressing transgenic mouse heart. J Pharmacol Exp Ther 1998; 287(2): 515-20.
61. Sun XH, Zhou ZX, Kang YJ. Attenuation of doxorubicin chronic toxicity in metallothionein-overexpressing transgenic mouse heart. Cancer Res 2001; 61(8): 3382-7.
62. Kang YJ. The antioxidant function of metallothionein in the heart. Proc Soc Exp Biol Med 1999; 222(3): 263-73.
63. Kang YJ. Antioxidant defense against anthracycline cardiotoxicity by metallothionein. Cardiovasc Toxicol 2007; 7(2): 95-100.
64. Yin XH, Wu HY, Chen Y, Kang YJ. Induction of antioxidants by Adriamycin in mouse heart. Biochem Pharmacol 1998; 56(1): 87-93.
65. Minotti G, Cairo G, Monti E. Role of iron in anthracycline cardiotoxicity: new tunes for an old song? Faseb J 1999; 13(2): 199-212.
66. Merten KE, Jiang YC, Kang YJ. Zinc inhibits doxorubicinactivated calcineurin signal transduction pathway in H9c2 embryonic rat cardiac cells. Exp Biol Med 2007; 232(5): 682-9.
67. Sutherland DEK, Stillman MJ. The "magic numbers'' of metallothionein. Metallomics 2011; 3(5): 444-63.
68. Margoshes M, Vallee BL. A cadmium protein from equine kidney cortex. J Am Chem Soc 1957; 79(17): 4813-4.
69. Vasak M, Meloni G. Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 2011; 16(7): 1067-78.
70. Thirumoorthy N, Sunder AS, Kumar KTM, Kumar MS, Ganesh GNK, Chatterjee M. A review of metallothionein isoforms and their role in pathophysiology. World J Surg Oncol 2011; 9: 1-7.
71. Vasak M. Advances in metallothionein structure and functions. J Trace Elem Med Bio 2005; 19(1): 13-7.
72. Zalewska M, Trefon J, Milnerowicz H. The role of metallothionein interactions with other proteins. Proteomics 2014; 14(11): 1343-56.
73. Andrews GK. Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol 2000; 59(1): 95-104.
74. Takahashi S. Molecular functions of metallothionein and its role in hematological malignancies. J Hematol Oncol 2012; 5: 1-8.
75. Park Y, Yu E. Expression of metallothionein-1 and metallothionein-2 as a prognostic marker in hepatocellular carcinoma. J Gastroen Hepatol 2013; 28(9): 1565-72.
76. Masters BA, Quaife CJ, Erickson JC, et al. Metallothionein-III is expressed in neurons that sequester zinc in synaptic vesicles J Neurosci 1994; 14(10): 5844-57.
77. Hoey JG, Garrett SH, Sens MA, Todd JH, Sens DA. Expression of MT-3 mRNA in human kidney, proximal tubule cell cultures, and renal cell carcinoma. Toxicol Lett 1997; 92(2): 149-60.
78. Meloni G, Zovo K, Kazantseva J, Palumaa P, Vasak M. Organization and assembly of metal-thiolate clusters in epitheliumspecific metallothionein-4. J Biol Chem 2006; 281(21): 14588-95.
79. Carpene E, Andream G, Isam G. Metallothionein functions and structural characteristics. J Trace Elem Med Bio 2007; 21: 35-9.
80. Raudenska M, Gumulec J, Podlaha O, et al. Metallothionein polymorphisms in pathological processes. Metallomics 2014; 6(1): 55-68.
81. Skutkova H, Babula P, Stiborova M, et al. Structure, polymorphisms and electrochemistry of mammalian metallothioneins – A review. Int J Electrochem Sci 2012; 7(12): 12415-31.
82. Coyle P, Philcox JC, Carey LC, Rofe AM. Metallothionein: The multipurpose protein. Cell Mol Life Sci 2002; 59(4): 627-47.
83. Krizkova S, Masarik M, Eckschlager T, Adam V, Kizek R. Effects of redox conditions and zinc(II) ions on metallothionein aggregation revealed by chip capillary electrophoresis. J Chromatogr A 2010; 1217(51): 7966-71.
84. Chubatsu LS, Meneghini R. Metallothionein protects DNA from oxidative damage. Biochem J 1993; 291: 193-8.
85. Moffatt P, Seguin C. Expression of the gene encoding metallothionein-3 in organs of the reproductive system. DNA Cell Biol 1998; 17(6): 501-10.
86. Cherian MG, Kang YJ. Metallothionein and liver cell regeneration. Exp Biol Med 2006; 231(2): 138-44.
87. Maret W. Zinc and sulfur: A critical biological partnership. Biochemistry 2004; 43(12): 3301-9.
88. Ruttkay-Nedecky B, Nejdl L, Gumulec J, et al. The role of metallothionein in oxidative stress. Int J Mol Sci 2013; 14(3): 6044-66.
89. Pinter TBJ, Stillman MJ. The zinc balance: Competitive zinc metalation of carbonic anhydrase and metallothionein 1A. Biochemistry 2014; 53(39): 6276-85.
90. Iszard MB, Liu J, Klassen CD. Effect of several metallothionein inducers on oxidative stress defense mechanisms in rats. Toxicology 1995; 104(1-3): 25-33.
91. Schwarz MA, Lazo JS, Yalowich JC, et al. Metallothionein protects against the cytotoxic and DNA-damaging effects of nitricoxide Proc Natl Acad Sci USA 1995; 92(10): 4452-6.
92. Satoh M, Kondo Y, Mita M, Nakagawa I, Naganuma A, Imura N. Prevention of carcinogenity of anticancer drugs by metallothionein induction Cancer Res 1993; 53(20): 4767-8.
93. Quesada AR, Byrnes RW, Krezoski SO, Petering DH. Direct reaction of H2O2 with sulfhydryl groups in HL-60 cells: Zincmetallothionein and other sites. Arch Biochem Biophys 1996; 334(2): 241-50.
94. Cai L, Cherian MG. Zinc-metallothionein protects from DNA damage induced by radiation better than glutathione and copper-or cadmium-metallothioneins. Toxicol Lett 2003; 136(3): 193-8.
95. Sabolic I, Breljak D, Skarica M, Herak-Kramberger CM. Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 2010; 23(5): 897-926.
96. Klaassen CD, Liu J. Metallothionein transgenic and knock-out mouse models in the study of cadmium toxicity. J Toxicol Sci 1998; 23(Suppl 2): 97-102.
97. Kowalska K, Zalewska ABM, Milnerowicz H. The influence of biological and environmental factors on metallothionein concentration in the blood. J Trace Elem Med Bio 2015; 29: 99-103.
98. Nordberg G, Jin TY, Wu XW, et al. Kidney dysfunction and cadmium exposure -Factors influencing dose-response relationships. J Trace Elem Med Bio 2012; 26(2-3): 197-200.
99. Nordberg M, Nordberg GF. Metallothioneins: Historical development and overview. In: Sigel A, Sigel H, Sigel RKO, Eds. Metallothioneins and Related Chelators: Metal Ions in Life Sciences. Cambridge: Royal Society of Chemistry 2009: pp. 544.
100. Lynes MA, Zaffuto K, Unfricht DW, Marusov G, Samson JS, Yin XY. The physiological roles of extracellular metallothionein. Exp Biol Med 2006; 231(9): 1548-54.
101. Cernei N, Heger Z, Gumulec J, et al. Sarcosine as a potential prostate cancer biomarker – A review. Int J Mol Sci 2013; 14(7): 13893-908.
102. Cherian MG, Jayasurya A, Bay BH. Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res-Fundam Mol Mech Mutagen 2003; 533(1-2): 201-9.
103. Ryan KM, Phillips AC, Vousden KH. Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol 2001; 13(3): 332-7.
104. Butcher HL, Kennette WA, Collins O, Zalups RK, Koropatnick J. Metallothionein mediates the level and activity of nuclear factor kappa B in murine fibroblasts. J Pharmacol Exp Ther 2004; 310(2): 589-98.
105. Orihuela R, Fernandez B, Palacios O, et al. Ferritin and metallothionein: dangerous liaisons. Chem Commun 2011; 47(44): 12155-7.
106. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
107. Cherian MG, Howell SB, Imura N, et al. Contemporary-issues in toxicology-role of metallothionein in carcinogenesis. Toxicol Appl Pharmacol 1994; 126(1): 1-5.
108. Eckschlager T, Adam V, Hrabeta J, Figova K, Kizek R. Metallothioneins and cancer. Curr Protein Pept Sci 2009; 10(4): 360-75.
109. Lai YY, Yip GWC, Bay BH. Targeting metallothionein for prognosis and treatment of breast cancer. Recent Pat Anti-Canc 2011; 6(2): 178-85.
110. Naito S, Yokomizo A, Koga H. Mechanisms of drug resistance in chemotherapy for urogenital carcinoma. Int J Urol 1999; 6(9): 427-39.
111. Tanner B, Pilch H, Schmidt M, Hengstler JG. Expression of metallothionein and glutathione in ovarian carcinomas. Geburtsh Frauenheilk 2002; 62(2): 145-54.
112. Wulfing C, van Ahlen H, Eltze E, Piechota H, Hertle L, Schmid KW. Metallothionein in bladder cancer: correlation of overexpression with poor outcome after chemotherapy. World J Urol 2007; 25(2): 199-205.
113. Mattern J, Volm M. Increased resistance to doxorubicin in human non-small cell lung carcinomas with metallothionein expression. Int J Oncol 1992; 1(6): 687-9.
114. DeVita VK, Lawrence TS, Rosenberg SA, DePinho MD, Weinberg RA. Cancer: Principles & Practice of Oncology. 9 Ed. Philadelphia: Lippincot Williams & Wilkins 2011.
115. Grein A, Spalla C, Canevazz G, Dimarco A. Descrizione e classificazione di un attiomicete (Streptomyces peucetius sp. nova) produttore di una sostanza ad attivita antitumorale -la daunomicina. Gior Microbiol 1963; 11(2): 109-18.
116. Bonadonna G, Monfardini S, De Lena M, Fossati-Bellani F. Clinical evaluation of adriamycin, a new antitumour antibiotic. Br Med J 1969; 3(5669): 503-6.
117. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004; 56(2): 185-229.
118. Robert J, Gianni L. Pharmacokinetics and metabolism of anthracyclines. Canc Surv 1993; 17: 219-52.
119. Danesi R, Fogli S, Gennari A, Conte P, Del Tacca M. Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharmacokinet 2002; 41(6): 431-44.
120. Robert J. Epirubicin. Drugs 1993; 45(2): 20-30.
121. Borchmann P, Hübel K, Schnell R, Engert A. Idarubicin: a brief overview on pharmacology and clinical use. Int J Clin Pharmacol Ther 1997; 35(2): 80-3.
122. Binaschi M, Bigioni M, Cipollone A, et al. Anthracyclines: Selected new developments. Curr Med Chem 2001; 1(2): 113-30.
123. Toffoli G, Sorio R, Aita P, et al. Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients. Clin Cancer Res 2000; 6(6): 2279-87.
124. Toffoli G, Simone F, Gigante M, Boiocchi M. Comparison of mechanisms responsible for resistance to idarubicin and daunorubicin in multidrug-resistant lovo cell-lines. Biochem Pharmacol 1994; 48(10): 1871-81.
125. Jonsson-Videsater K, Andersson G, Bergh J, Paul C. Doxorubicinresistant, MRP1-expressing U-1285 cells are sensitive to idarubicin. Ther Drug Monit 2003; 25(3): 331-9.
126. Lothstein L, Israel M, Sweatman TW. Anthracycline drug targeting: cytoplasmic versus nuclear -A fork in the road. Drug Resist Update 2001; 4(3): 169-77.
127. Koh E, Ueda Y, Nakamura T, Kobayashi A, Katsuta S, Takahashi H. Apoptosis in young rats with adriamycin-induced cardiomyopathy -Comparison with pirarubicin, a new anthracycline derivative. Pediatr Res 2002; 51(2): 256-9.
128. Dhingra K, Frye D, Newman RA, et al. Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer. Clin Cancer Res 1995; 1(7): 691-7.
129. Niitsu N, Yamazaki J-I, Nakayama M, Umeda M. Pirarubicininduced myocardial damage in elderly patients with non-hodgkin's lymphoma. Nip Ron Igakkai Zas 1998; 35(5): 358-62.
130. Case DC, Ervin TJ, Boyd MA, Bove LG, Sonneborn HL, Paul SD. Phase-II study of aclarubicin in acute myeloblastic-leukemia. Am J Clin Oncol-Canc 1987; 10(6): 523-6.
131. Wojnar J, Mandecki M, Wnuk-Wojnar AM, Hołowiecki J. Clinical studies on aclacinomycin A cardiotoxicity in adult patients with acute non lymphoblastic leukaemia. Folia Haematol 1989; 116(2): 297-303.
132. Dabich L, Bull FE, Beltran G, et al. Phase-II evaluation of aclarubicin in refractory adult acute-leukemia -A southwestoncology-group study. CancTreat Rep 1986; 70(8): 967-9.
133. Estorch M, Carrio I, Martinezduncker D, et al. Myocyte celldamage after administration of doxorubicin or mitoxantrone in breast-cancer patients assessed by in-111 antimyosin monoclonalantibody studies. J Clin Oncol 1993; 11(7): 1264-8.
134. Thomas X, Le QH, Fiere D. Anthracycline-related toxicity requiring cardiac transplantation in long-term disease-free survivors with acute promyelocytic leukemia. Ann Hematol 2002; 81(9): 504-7.
135. Bedrnicek J, Vicha A, Jarosova M, et al. Characterization of drugresistant neuroblastoma cell lines by comparative genomic hybridization. Neoplasma 2005; 52(5): 415-9.
136. Huska D, Adam V, Babula P, et al. Square wave voltammetry as a tool for investigation of doxorubicin interactions with DNA isolated from neuroblastoma cells. Electroanalysis 2009; 21(3-5): 487-94.
137. Schwartz HS, Parker NB. Initial biotransformations of daunorubicin to aglycones by rat-liver microsomes. Cancer Res 1981; 41(6): 2343-8.
138. Singal PK, Iliskovic N, Li TM, Kumar D. Adriamycin cardiomyopathy: pathophysiology and prevention. Febs J 1997; 11(12): 931-6.
139. Kizek R, Adam V, Hrabeta J, et al. Anthracyclines and ellipticines as DNA-damaging anticancer drugs: Recent advances. Pharmacol Ther 2012; 133(1): 26-39.
140. Myers C. The role of iron in doxorubicin-induced cardiomyopathy. Semin Onco 1998; 25(4): 10-4.
141. Xu XX, Persson HL, Richardson DR. Molecular pharmacology of the interaction of anthracyclines with iron. Mol Pharmacol 2005; 68(2): 261-71.
142. Sterba M, Popelova O, Vavrova A, et al. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Sign 2013; 18(8): 899-929.
143. Menna P, Paz OG, Chello M, Covino E, Salvatorelli E, Minotti G. Anthracycline cardiotoxicity. Expert Opin Drug Saf 2012; 11: S21-36.
144. Sieswerda E, Kremer LCM, Caron HN, van Dalen EC. The use of liposomal anthracycline analogues for childhood malignancies: A systematic review. Eur J Cancer 2011; 47(13): 2000-8.
145. Perez-Arnaiz C, Busto N, Leal JM, Garcia B. New insights into the mechanism of the DNA/doxorubicin interaction. J Phys Chem B 2014; 118(5): 1288-95.
146. Nikitovic D, Juranek I, Wilks MF, Tzardi M, Tsatsakis A, Tzanakakis GN. Anthracycline-dependent cardiotoxicity and extracellular matrix remodeling. Chest 2014; 146(4): 1123-30.
147. Zhou QB, Turnbull KD. Phosphodiester alkylation with a quinone methide. J Org Chem 1999; 64(8): 2847-51.
148. Taatjes DJ, Gaudiano G, Koch TH. Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron. Chem Res Toxicol 1997; 10(9): 953-61.
149. Podell ER, Harrington DJ, Taatjes DJ, Koch TH. Crystal structure of epidoxorubicin-formaldehyde virtual crosslink of DNA and evidence for its formation in human breast-cancer cells. Acta Crystallogr Sect D-Biol Crystallogr 1999; 55: 1516-23.
150. Koch TH, Barthel BL, Kalet BT, Rudnicki DL, Post GC, Burkhart DJ. Anthracycline-formaidehyde conjugates and their targeted prodrugs. In: Krohn K, Ed. Anthracycline Chemistry and Biology II: Mode of Action, Clinical Aspects and New Drugs. Springer-Verlag Berlin 2008: 141-70.
151. Brazzolotto X, Andriollo M, Guiraud P, Favier A, Moulis JM. Interactions between doxorubicin and the human iron regulatory system. Biochim Biophys Acta-Mol Cell Res 2003; 1593(2-3): 209-18.
152. Huska D, Adam V, Burda J, et al. Electrochemical and computational study of doxorubicin interactions with DNA. Febs J 2009; 276: 109-.
153. Subramanian R, Asmawi MZ, Sadikun A. A bitter plant with a sweet future? A comprehensive review of an oriental medicinal plant: Andrographis paniculata. Phytochem Rev 2012; 11(1): 39-75.
154. Deng SW, Yan TD, Jendrny C, Nemecek A, Vincetic M, Godtel-Armbrust U, et al. Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms. BMC Cancer 2014; 14: 1-11.
155. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis. Eur J Cancer 2013; 49(13): 2900-9.
156. Suzuki T, Ichihara M, Hyodo K, et al. Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin. Int J Pharm 2014; 476(12): 205-12.
157. Safra T. Cardiac safety of liposomal anthracyclines. Oncologist 2003; 8: 17-24.
158. Rahman AM, Yusuf SW, Ewer MS. Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation. Int J Nanomed 2007; 2(4): 567-83.
159. Nazir S, Hussain T, Ayub A, Rashid U, MacRobert AJ. Nanomaterials in combating cancer: Therapeutic applications and developments. Nanomed Nanotechnol 2014; 10(1): 19-34.
160. Caruso JA, O'Connor N. Metallomics: integrating research related to biometals-a journal for an emerging community. Metallomics 2009; 1(1): 14-24.
161. Gaetke LM, Chow-Johnson HS, Chow CK. Copper: toxicological relevance and mechanisms. Arch Toxicol 2014; 88(11): 1929-38.
162. Liuzzi JP, Guo L, Yoo C, Stewart TS. Zinc and autophagy. Biometals 2014; 27(6): 1087-96.
163. Osredkar J, Sustar N. Copper and Zinc, Biological role and significance of copper/zinc imbalance. J Clin Toxicol 2011; S3: 1-18.
164. Leoni G, Rosato A, Perozzi G, Murgia C. Zinc proteome interaction network as a model to identify nutrient-affected pathways in human pathologies. Genes Nutr 2014; 9(6): 1-9.
165. Efeovbokhan N, Bhattacharya SK, Ahokas RA, et al. Zinc and the prooxidant heart failure phenotype. J Cardiovasc Pharmacol 2014; 64(4): 393-400.
166. Apak R, Gucclu K, Ozyurek M, Bektasoglu B, Bener M. Cupric Ion Reducing Antioxidant Capacity Assay for Antioxidants in Human Serum and for Hydroxyl Radical Scavengers. In: Armstrong D, Ed. Advanced Protocols in Oxidative Stress II. Totowa: Humana Press Inc 2010: 215-39.
167. Zhao WJ, An CH, Long DD, Zhang ZQ, Han JR. Effect of copperinduced oxidative stress on sclerotial differentiation and antioxidants contents of Penicillium thomii Q1. J Basic Microbiol 2014; 54(12): 1395-402.
168. Kimura T, Okumura F, Oguro I, et al. Metal response elementbinding transcription factor-1 is activated by degradation of metallothionein. J Health Sci 2009; 55(1): 72-6.
169. Wang JX, Song Y, Elsherif L, et al. Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation 2006; 113(4): 544-54.
170. Bohuslavova R, Skvorova L, Sedmera D, Semenza GL, Pavlinkova G. Increased susceptibility of HIF-1 alpha heterozygous-null mice to cardiovascular malformations associated with maternal diabetes. J Mol Cell Cardiol 2013; 60: 129-41.
171. Kumar SD, Vijaya M, Samy RP, et al. Zinc supplementation prevents cardiomyocyte apoptosis and congenital heart defects in embryos of diabetic mice. Free Radical Bio Med 2012; 53(8): 1595-606.
172. Ali MM, Frei E, Straub J, Breuer A, Wiessler M. Induction of metallothionein by zinc protects from daunorubicin toxicity in rats. Toxicology 2002; 179(12): 85-93.
173. Kang YJ. The antioxidant function of metallothionein in the heart. Proc Soc Exp Biol Med 1999; 222(3): 263-73.
174. Kang YJ, Chen Y, Epstein PN. Suppression of doxorubicin cardiotoxicity by overexpression of catalase in the heart of transgenic mice. J Biol Chem 1996; 271(21): 12610-6.
175. Satoh M, Naganuma A, Imura N. Modulation of adriamycin toxicity by tissue-specific induction of metallothionein synthesis in mice. Life Sci 2000; 67(6): 627-34.
176. Wang GW, Kang YJ. Inhibition of doxorubicin toxicity in cultured neonatal mouse cardiomyocytes with elevated metallothionein levels. J Pharmacol Exp Ther 1999; 288(3): 938-44.
177. Kang YJ. Antioxidant defense against anthracycline cardiotoxicity by metallothionein. Cardiovasc Toxicol 2007; 7(2): 95-100.
178. Guo R, Wu K, Chen J, et al. Exogenous hydrogen sulfide protects against doxorubicin-induced inflammation and cytotoxicity by inhibiting p38MAPK/NFkappaB pathway in H9c2 cardiac cells. Cell Physiol Biochem 2013; 32(6): 1668-80.
179. Kim DS, Kim HR, Woo ER, Hong ST, Chae HJ, Chae SW. Inhibitory effects of rosmarinic acid on adriamycin-induced apoptosis in H9c2 cardiac muscle cells by inhibiting reactive oxygen species and the activations of c-Jun N-terminal kinase and extracellular signal-regulated kinase. Biochem Pharmacol 2005; 70(7): 1066-78.
180. Kim DS, Woo ER, Chae SW, et al. Plantainoside D protects adriamycin-induced apoptosis in H9c2 cardiac muscle cells via the inhibition of ROS generation and NF-kappaB activation. Life Sci 2007; 80(4): 314-23.
181. Nayak PG, Paul P, Bansal P, Kutty NG, Pai KS. Sesamol prevents doxorubicin-induced oxidative damage and toxicity on H9c2 cardiomyoblasts. J Pharm Pharmacol 2013; 65(7): 1083-93.
182. Wang XL, Wang X, Xiong LL, et al. Salidroside improves doxorubicin-induced cardiac dysfunction by suppression of excessive oxidative stress and cardiomyocyte apoptosis. J Cardiovasc Pharmacol 2013; 62(6): 512-23.
183. Arunachalam S, Kim SY, Lee SH, et al. Davallialactone protects against adriamycin-induced cardiotoxicity in vitro and in vivo. J Nat Med 2012; 66(1): 149-57.
184. Li T, Danelisen I, Bello-Klein A, Singal PK. Effects of probucol on changes of antioxidant enzymes in adriamycin-induced cardiomyopathy in rats. Cardiovasc Res 2000; 46(3): 523-30.
185. Park S, Yoon J, Bae S, et al. Therapeutic use of H2O2-responsive anti-oxidant polymer nanoparticles for doxorubicin-induced cardiomyopathy. Biomaterials 2014; 35(22): 5944-53.
186. Kaiserova H, Simunek T, Sterba M, et al. New iron chelators in anthracycline-induced cardiotoxicity. Cardiovasc Toxicol 2007; 7(2): 145-50.
187. Simunek T, Sterba M, Popelova O, et al. Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone. Br J Pharmacol 2008; 155(1): 138-48.
188. Bast A, Haenen GR, Bruynzeel AM, Van der Vijgh WJ. Protection by flavonoids against anthracycline cardiotoxicity: from chemistry to clinical trials. Cardiovasc Toxicol 2007; 7(2): 154-9.
189. Bast A, Kaiserova H, den Hartog GJ, Haenen GR, van der Vijgh WJ. Protectors against doxorubicin-induced cardiotoxicity: flavonoids. Cell Biol Toxicol 2007; 23(1): 39-47.
190. Dickey JS, Gonzalez Y, Aryal B, et al. Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model. PLoS One 2013; 8(8): 1-14.
191. Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Fut Cardiol 2012; 8(4): 647-70.
192. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-Associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 2007; 25(5): 493-500.
193. Viarengo A, Burlando B, Ceratto N, Panfoli I. Antioxidant role of metallothioneins: a comparative overview. Cell Mol Biol 2000; 46(2): 407-17.
194. Feng W, Benz FW, Cai J, Pierce WM, Kang YJ. Metallothionein disulfides are present in metallothionein-overexpressing transgenic mouse heart and increase under conditions of oxidative stress. J Biol Chem 2006; 281(2): 681-7.
195. Shuai Y, Guo J, Dong Y, et al. Global gene expression profiles of MT knockout and wild-type mice in the condition of doxorubicininduced cardiomyopathy. Toxicol Lett 2011; 200(1-2): 77-87.
196. Guo J, Guo Q, Fang H, et al. Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1alpha pathway. Eur J Pharmacol 2014; 737: 117-24.
197. Sun X, Kang YJ. Prior increase in metallothionein levels is required to prevent doxorubicin cardiotoxicity. Exp Biol Med 2002; 227(8): 652-7.
198. Shuai Y, Guo JB, Peng SQ, et al. Metallothionein protects against doxorubicin-induced cardiomyopathy through inhibition of superoxide generation and related nitrosative impairment. Toxicol Lett 2007; 170(1): 66-74.
199. Krizkova S, Ryvolova M, Hrabeta J, et al. Metallothioneins and zinc in cancer diagnosis and therapy. Drug Metab Rev 2012; 44(4): 287-301.
200. Choi CH. Cloning and functional study of a novel human metallothionein-I isoform induced by paraquat. Biochem Biophys Res Commun 2003; 304(2): 236-40.
201. Margalit O, Simon AJ, Yakubov E, et al. Zinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function. Int J Cancer 2012; 131(4): E562-E8.
202. Cirone M, Garufi A, Di Renzo L, Granato M, Faggioni A, D'Orazi G. Zinc supplementation is required for the cytotoxic and immunogenic effects of chemotherapy in chemoresistant p53-functionally deficient cells. Oncoimmunology 2013; 2(9): 1-9.
203. Zablocki D, Sadoshima J. Angiotensin II and Oxidative Stress in the Failing Heart. Antioxid Redox Sign 2013; 19(10): 1095-109.
204. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury -Part I: Basic mechanisms and in vivo monitoring of ROS. Circulation 2003; 108(16): 1912-6.
205. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol-Heart C 2011; 301(6): H2181-H90.
206. Guo J, Guo Q, Fang H, et al. Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1 alpha pathway. European J Pharmacol 2014; 737: 117-24.
207. Cong WT, Zhao T, Zhu ZX, et al. Metallothionein prevents cardiac pathological changes in diabetes by modulating nitration and inactivation of cardiac ATP synthase. J Nutr Biochem 2014; 25(4): 463-74.
208. Zhou SS, Yin X, Zheng Y, et al. Metallothionein prevents intermittent hypoxia-induced cardiac endoplasmic reticulum stress and cell death likely via activation of Akt signaling pathway in mice. Toxicol Lett 2014; 227(2): 113-23.
209. Yang LF, Hu N, Jiang SS, et al. Heavy metal scavenger metallothionein attenuates ER stress-induced myocardial contractile anomalies: Role of autophagy. Toxicol Lett 2014; 225(3): 333-41.
210. Oshima Y, Fujio Y, Nakanishi T, Itoh N, Yamamoto Y, Negoro S, et al. STAT3 mediates cardioprotection against ischemia/ reperfusion injury through metallothionein induction in the heart. Cardiovasc Res 2005; 65(2): 428-35.
211. Yin X, Zhou SS, Zheng Y, et al. Metallothionein as a compensatory component prevents intermittent hypoxia-induced cardiomyopathy in mice. Toxicol Appl Pharmacol 2014; 277(1): 58-66.
212. Krizkova S, Ryvolova M, Hrabeta J, et al. Metallothioneins and zinc in cancer diagnosis and therapy. Drug Metab Rev 2012; 44(4): 287-301.
213. Tarapore P, Shu Y, Guo PX, Ho SM. Application of Phi29 motor pRNA for targeted therapeutic delivery of siRNA silencing metallothionein-IIA and survivin in ovarian cancers. Mol Ther 2011; 19(2): 386-94.
214. Fu Z, Guo JB, Jing L, Li RS, Zhang TF, Peng SQ. Enhanced toxicity and ROS generation by doxorubicin in primary cultures of cardiomyocytes from neonatal metallothionein-I/II null mice. Toxicol Vitro 2010; 24(6): 1584-91.
215. Guo JB, Peng SQ. Enhanced apoptosis and myocardial injuries in metallothionein-null mice by doxorubicin treatment. Acta Pharmacol Sin 2006; 27: 142
216. Yang HY, Wang YM, Peng SQ. Metallothionein-I/II null cardiomyocytes are sensitive to Fusarium mycotoxin butenolideinduced cytotoxicity and oxidative DNA damage. Toxicon 2010; 55(7): 1291-6.
217. Choi CH. Cloning and functional study of a novel human metallothionein-I isoform induced by paraquat. Biochem Biophys Res Commun 2003; 304(2): 236-40.
218. Sato M, Sasaki M, Hojo H. Tissue specific induction of metallothionein synthesis by tumor-necrosis-factor-alpha. Res Commun Chem Pathol Pharm 1992; 75(2): 159-72.
219. Chen QM, Alexander D, Sun HP, et al. Corticosteroids inhibit cell death induced by doxorubicin in cardiomyocytes: Induction of antiapoptosis, antioxidant, and detoxification genes. Mol Pharmacol 2005; 67(6): 1861-73.