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protection vs. anthracycline-induced cardiac damage--food for thought
Three interesting articles on manganese super oxide dismutase (no, don't go out to the health food store and buy it yet!) and tamoxifen (via SOD) which may help protect the heart against anthracycline- induced damage.
As the story unfolds, researchers and oncologists can "get ideas" ie, generally accepted practice is not to treat with antihormonals at the same time as chemo (usually started after radiation therapy)-- but perhaps it would be a good idea with an anthracycline-containing regimens
It is by raising questions on the "status quo" and dogma that progress is made.
Since Dr. Slamon thinks it is those who are positive for TOPO II in whom anthracyclines are most needed, perhaps a trial of tamoxifen during chemo
in those with estrogen receptors is warranted.
Just food for thought!
1: Cardiovasc Res. 2006 Jan;69(1):186-97. Epub 2005 Sep 12.
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The protective roles of nitric oxide and superoxide dismutase in adriamycin-induced cardiotoxicity.
Cole MP, Chaiswing L, Oberley TD, Edelmann SE, Piascik MT, Lin SM, Kiningham KK, St Clair DK.
Graduate Centers for Toxicology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, 464 Health Sciences Research Building, Lexington, KY 40536, USA.
OBJECTIVE: Treatment with adriamycin (ADR) is associated with cardiotoxicity mediated through the generation of superoxide (O2*-). Because nitric oxide (*NO) reacts with O2*-, generating peroxynitrite, we hypothesized that decreased *NO production would lead to protection in acute cardiac injury. METHODS: We investigated the role of decreased *NO levels in exacerbation of ADR-induced cardiotoxicity in vivo using iNOS (-/-) mice. Pathology, biochemical injury markers, and cardiac function were used to assess ADR-induced cardiac injury. RESULTS: Ultrastructural analysis demonstrated that iNOS (-/-) mice exhibited extensive cytoplasmic swelling and degeneration of mitochondria when compared to wildtype mice following treatment with ADR. Mice lacking iNOS exhibited a decrease in resting indices of cardiac function as well as an impairment in the positive inotropic actions of isoproterenol following treatment with ADR compared to nTg mice. Cardiac troponin, creatine phosphokinase, and lactate dehydrogenase levels were significantly increased after treatment in iNOS (-/-) mice as compared to controls and wildtype mice. CONCLUSIONS: These results indicate that a lack of *NO production by iNOS caused significantly enhanced cardiac injury. However, when iNOS (-/-) mice were crossed with manganese superoxide dismutase (MnSOD)-overexpressing animals, mitochondrial injury was ameliorated to the level of the wild type. These findings suggest that reduction of *NO levels mediated by ADR treatment leads to increased cardiac mitochondrial injury that can be attenuated by a compensatory increase in MnSOD.
1: J Mol Cell Cardiol. 2005 Nov;39(5):792-803. Epub 2005 Sep 2.
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Induction of manganese superoxide dismutase (MnSOD) mediates cardioprotective effect of tamoxifen (TAM).
Daosukho C, Ittarat W, Lin SM, Sawyer DB, Kiningham K, Lien YC, St Clair DK.
Graduate Center for Toxicology, University of Kentucky, 458 Health Science Research Building, Lexington, KY 40536, USA.
Tamoxifen (TAM), a synthetic nonsteroidal antiestrogen effectively and widely used for breast cancer treatment, is known to have antioxidant and cardioprotective effects, but whether the beneficial cardiovascular effect of TAM is linked to its antioxidant effect is unknown. In this study, we investigated the effect of TAM on the levels of manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, in cardiac tissues and cardiomyocytes. TAM treatment induced MnSOD expression in vitro and in vivo. Cardiomyocytes isolated from TAM-pretreated mice also had higher MnSOD levels and fewer apoptotic cells compared to cardiomyocytes from control mice after adriamycin (ADR) treatment. To further confirm the role of MnSOD in the protection against ADR in cardiomyocytes, we used cardiomyocytes isolated from MnSOD knock-out (MnSOD(+/-)), wild-type (NTg) and human MnSOD transgenic (TgH) mice. TUNEL assay indicated that the percentage of cells undergoing apoptosis after ADR treatment was significantly greater in MnSOD(+/-) than in NTg or TgH cardiomyocytes. 3-[4, 5-Dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay showed that basal level of mitochondrial function was lower in MnSOD(+/-) cardiomyocytes than in NTg or TgH, and that MnSOD(+/-) was more sensitive to ADR. ADR treatment increased caspase activity, which was significantly higher in MnSOD(+/-) than in NTg or TgH cardiomyocytes. These results suggested that TAM-induced MnSOD expression is at least, in part, contribute to the cardioprotective effects of TAM.
1: Oncogene. 2002 May 16;21(22):3603-10.
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Tamoxifen enhancement of TNF-alpha induced MnSOD expression: modulation of NF-kappaB dimerization.
Daosukho C, Kiningham K, Kasarskis EJ, Ittarat W, St Clair DK.
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, KY 40536, USA.
Manganese superoxide dismutase (MnSOD) has been shown to suppress the development of cancer. Tamoxifen (TAM), a nonsteroidal anti-estrogen that is widely used in chemotherapy, is known to be a modulator of antioxidant status. However, the mechanism by which TAM mediates antioxidant enzyme induction remains unclear. In this study we investigated TAM enhancement of MnSOD induction by TNF-alpha. The results show that co-treatment with TAM and TNF-alpha increases the MnSOD promoter/enhancer driven luciferase activity, MnSOD mRNA and protein levels. Interestingly, co-treatment with TAM and TNF-alpha drastically decreases the binding activity of the p50/p50 homodimer and increases that of the p50/p65 heterodimer compared to TNF-alpha alone. This change in DNA binding could not be attributed to a decrease in the level of p50, its precursor, p105, or its inhibitors. Furthermore, TAM did not enhance degradation of IkappaB-alpha. These results suggest that p50/p50 homodimer may act as an inhibitory complex of MnSOD expression. Modulation of the DNA binding activity in favor of the p50/p65 complex may enhance NF-kappaB mediated induction of MnSOD by TAM. These findings reveal a potential novel mechanism for the induction of the human MnSOD gene.
PMID: 12032862 [PubMed - indexed for MEDLINE]
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