The Protective Role of Manganese Superoxide Dismutase Against Adriamycin-induced Acute Cardiac Toxicity in Transgenic Mice

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1996 Sep 1

PMID 8787689

Citations 148

Authors

H C Yen

T D Oberley

S Vichitbandha

Y S Ho

D K St Clair

Affiliations

Soon will be listed here.

Abstract

Adriamycin (ADR) is a potent anticancer drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity and the intracellular target for ADR-induced cardiac toxicity are still not well understood. We produced three transgenic mice lines expressing increased levels of human manganese superoxide dismutase (MnSOD), a mitochondrial enzyme, as an animal model to investigate the role of ADR-mediated free radical generation in mitochondria. The human MnSOD was expressed, functionally active, and properly transported into mitochondria in the heart of transgenic mice. The levels of copper-zinc SOD, catalase, and glutathione peroxidase did not change in the transgenic mice. Electron microscopy revealed dose-dependent ultrastructural alterations with marked mitochondrial damage in nontransgenic mice treated with ADR, but not in the transgenic littermates. Biochemical analysis indicated that the levels of serum creatine kinase and lactate dehydrogenase in ADR-treated mice were significantly greater in nontransgenic than their transgenic littermates expressing a high level of human MnSOD after ADR treatment. These results support a major role for free radical generation in ADR toxicity as well as suggesting mitochondria as the critical site of cardiac injury.

Citing Articles

Evolution of Theories on Doxorubicin-Induced Late Cardiotoxicity-Role of Topoisomerase.

Szponar J, Ciechanski E, Ciechanska M, Dudka J, Mandziuk S Int J Mol Sci. 2025; 25(24.

PMID: 39769331 PMC: 11678604. DOI: 10.3390/ijms252413567.

Post-sepsis chronic muscle weakness can be prevented by pharmacological protection of mitochondria.

Kingren M, Keeble A, Galvan-Lara A, Ogle J, Ungvari Z, St Clair D Mol Med. 2024; 30(1):221.

PMID: 39563237 PMC: 11577827. DOI: 10.1186/s10020-024-00982-w.

A Cardiac-Targeting and Anchoring Bimetallic Cluster Nanozyme Alleviates Chemotherapy-Induced Cardiac Ferroptosis and PANoptosis.

Xing J, Ma X, Yu Y, Xiao Y, Chen L, Yuan W Adv Sci (Weinh). 2024; 12(1):e2405597.

PMID: 39467094 PMC: 11714205. DOI: 10.1002/advs.202405597.

Trace elements and metal nanoparticles: mechanistic approaches to mitigating chemotherapy-induced toxicity-a review of literature evidence.

Famurewa A, George M, Ukwubile C, Kumar S, Kamal M, Belle V Biometals. 2024; 37(6):1325-1378.

PMID: 39347848 DOI: 10.1007/s10534-024-00637-7.

A longitudinal evaluation of oxidative stress - mitochondrial dysfunction - ferroptosis genes in anthracycline-induced cardiotoxicity.

Qianqian R, Peng Z, Licai Z, Ruizhi Z, Tianhe Y, Xiangwen X BMC Cardiovasc Disord. 2024; 24(1):350.

PMID: 38987722 PMC: 11234563. DOI: 10.1186/s12872-024-03967-z.

References

Lawrence R, Burk R . Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976; 71(4):952-8. DOI: 10.1016/0006-291x(76)90747-6. View

Weisiger R, Fridovich I . Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization. J Biol Chem. 1973; 248(13):4793-6. View

Fridovich I . The biology of oxygen radicals. Science. 1978; 201(4359):875-80. DOI: 10.1126/science.210504. View

Chirgwin J, Przybyla A, MacDonald R, Rutter W . Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979; 18(24):5294-9. DOI: 10.1021/bi00591a005. View

Doroshow J . Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 1983; 43(2):460-72. View

Marklund S . Human copper-containing superoxide dismutase of high molecular weight. Proc Natl Acad Sci U S A. 1982; 79(24):7634-8. PMC: 347402. DOI: 10.1073/pnas.79.24.7634. View

Mimnaugh E, Trush M, Bhatnagar M, Gram T . Enhancement of reactive oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin. Biochem Pharmacol. 1985; 34(6):847-56. DOI: 10.1016/0006-2952(85)90766-x. View

Gunning P, Leavitt J, MUSCAT G, Ng S, Kedes L . A human beta-actin expression vector system directs high-level accumulation of antisense transcripts. Proc Natl Acad Sci U S A. 1987; 84(14):4831-5. PMC: 305199. DOI: 10.1073/pnas.84.14.4831. View

Ceballos I, Delabar J, Nicole A, Lynch R, Hallewell R, Kamoun P . Expression of transfected human CuZn superoxide dismutase gene in mouse L cells and NS20Y neuroblastoma cells induces enhancement of glutathione peroxidase activity. Biochim Biophys Acta. 1988; 949(1):58-64. DOI: 10.1016/0167-4781(88)90054-1. View

10.

Singal P, Deally C, Weinberg L . Subcellular effects of adriamycin in the heart: a concise review. J Mol Cell Cardiol. 1987; 19(8):817-28. DOI: 10.1016/s0022-2828(87)80392-9. View

11.

Ho Y, Crapo J . Isolation and characterization of complementary DNAs encoding human manganese-containing superoxide dismutase. FEBS Lett. 1988; 229(2):256-60. DOI: 10.1016/0014-5793(88)81136-0. View

12.

Powis G . Free radical formation by antitumor quinones. Free Radic Biol Med. 1989; 6(1):63-101. DOI: 10.1016/0891-5849(89)90162-7. View

13.

Marcillat O, Zhang Y, Davies K . Oxidative and non-oxidative mechanisms in the inactivation of cardiac mitochondrial electron transport chain components by doxorubicin. Biochem J. 1989; 259(1):181-9. PMC: 1138489. DOI: 10.1042/bj2590181. View

14.

Spitz D, Oberley L . An assay for superoxide dismutase activity in mammalian tissue homogenates. Anal Biochem. 1989; 179(1):8-18. DOI: 10.1016/0003-2697(89)90192-9. View

15.

Kelner M, Bagnell R . Alteration of endogenous glutathione peroxidase, manganese superoxide dismutase, and glutathione transferase activity in cells transfected with a copper-zinc superoxide dismutase expression vector. Explanation for variations in paraquat resistance. J Biol Chem. 1990; 265(19):10872-5. View

16.

Olson R, Mushlin P . Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J. 1990; 4(13):3076-86. View

17.

St Clair D, Holland J . Complementary DNA encoding human colon cancer manganese superoxide dismutase and the expression of its gene in human cells. Cancer Res. 1991; 51(3):939-43. View

18.

Ogura R, Sugiyama M, Haramaki N, Hidaka T . Electron spin resonance studies on the mechanism of adriamycin-induced heart mitochondrial damages. Cancer Res. 1991; 51(13):3555-8. View

19.

Laird P, Zijderveld A, Linders K, Rudnicki M, Jaenisch R, Berns A . Simplified mammalian DNA isolation procedure. Nucleic Acids Res. 1991; 19(15):4293. PMC: 328579. DOI: 10.1093/nar/19.15.4293. View

20.

Cini Neri G, Neri B, Bandinelli M, Del Tacca M, Danesi R, Riccardi R . Anthracycline cardiotoxicity: in vivo and in vitro effects on biochemical parameters and heart ultrastructure of the rat. Oncology. 1991; 48(4):327-33. DOI: 10.1159/000226952. View