Adriamycin stimulated superoxide formation in submitochondrial particles

Thayer, W. S.

doi:10.1016/0009-2797(77)90050-3

Cited by 246 publications

(60 citation statements)

References 28 publications

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“…If doxorubicin increases cardiac superoxide anion generation; the potential exists for hydrogen peroxide formation at a time when peroxide removal is impaired; a hydrogen peroxide concentration could then be reached that would exceed the detoxifying ability of the myocardial cell (3).…”

Section: Discussionmentioning

confidence: 99%

“…Although the mechanism of doxorubicin cardiac toxicity is unknown, several recent studies have demonstrated the conversion ofdoxorubicin to a free radical metabolite by cardiac mitochondria and by liver and cardiac microsomes (3,4). This free radical metabolite has been shown to reduce molecular oxygen to superoxide anion and to initiate lipid peroxidation in vitro (5).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enzymatic Defenses of the Mouse Heart Against Reactive Oxygen Metabolites

Doroshow¹,

Locker²,

Myers³

1980

J. Clin. Invest.

645

253

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A B S T R A C T The endogenous defenses ofthe mouse heart against reactive oxygen metabolites were investigated. The activities of three enzymes capable of detoxifying activated oxygen were determined in both the heart and liver; cardiac muscle contains 150 times less catalase and nearly four times less superoxide dismutase than liver. Glutathione peroxidase activities were, however, similar to the two tissues. Assay of glutathione peroxidase in the heart after 6 wk of selenium depletion with both hydrogen peroxide and cumene hydroperoxide as substrates revealed a >80% drop in enzyme activity and gave no indication that murine cardiac tissue contains nonselenium-dependent glutathione peroxidase. The selenium-deficient state, which was characterized by markedly decreased cardiac glutathione peroxidase levels, led to significantly enhanced doxorubicin toxicity at a dose of 15 mg/kg i.p. Doxorubicin administration in selenium-sufficient animals resulted in a dose-dependent decrease in cardiac glutathione peroxidase activity; the decrease in enzyme activity lasted 72 h after 15 mg/kg i.p. In contrast, cardiac superoxide dismutase and hepatic superoxide dismutase and glutathione peroxidase were unaffected by this dose of doxorubicin.These results suggest that the major pathway in cardiac tissue for detoxification of reactive oxygen metabolites is via the concerted action of superoxide

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enzymatic Defenses of the Mouse Heart Against Reactive Oxygen Metabolites

Doroshow¹,

Locker²,

Myers³

1980

J. Clin. Invest.

645

253

View full text Add to dashboard Cite

show abstract

“…Unfortunately, the total dose of these agents that can be administered is severely limited by a unique type of cardiac toxicity which may be the direct result of drug-induced free radical formation [2,3]. Both cardiac sarcosomes [2] and mitochondria [2,3] can reduce ADR and daunorubicin to their respective semiquinones, initiating a free radical cascade which heart tissue, with its Iimited antioxidant defenses 141, seems unable to resist.…”

Section: Introductionmentioning

confidence: 99%

“…Both cardiac sarcosomes [2] and mitochondria [2,3] can reduce ADR and daunorubicin to their respective semiquinones, initiating a free radical cascade which heart tissue, with its Iimited antioxidant defenses 141, seems unable to resist. Thayer [3] suggested initially that NADH dehydrogenase was the mitochondrial site of ADR reduction; however, a detailed study of this proposal as well as an investigation of the range of drug-related oxygen radical metabolism by mitochondria has not previously been conducted.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial NADH dehydrogenase‐catalyzed oxygen radical production by adriamycin, and the relative inactivity of 5‐iminodaunorubicin

1983

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“…Besides the events essential for protein biosynthesis and cell proliferation, the free radical formation is proposed as another cytolethal mechanism triggered by DOX. [1][2][3] Cellular reductases such as cytochrome P450 reductase 4) and xanthine oxidase 5) catalyze the one-electron reduction of the p-quinone structure in the anthraquinone ring of DOX into a semiquinone radical intermediate, which in turn reacts with molecular oxygen to yield superoxide anion radical. The radical is further converted into a more potent oxidizing agent hydroxyl radical, and thereby oxidatively modifies intracellular components such as nucleic acids, lipids and proteins, finally leading to the cancer cell death.…”

Section: Up-regulation Of Carbonyl Reductase 1 Renders Development Ofmentioning

confidence: 99%

Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

Matsunaga

Kezuka

Morikawa

et al. 2015

Biological & Pharmaceutical Bulletin

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Doxorubicin (DOX) is widely used for the treatment of a wide range of cancers such as breast and lung cancers, and malignant lymphomas, but is generally less efficacious in gastrointestinal cancers. The most accepted explanation for the DOX refractoriness is its resistance development. Here, we established DOX-resistant phenotypes of human gastric MKN45 and colon LoVo cells by continuous exposure to incremental concentrations of the drug. While the parental MKN45 and LoVo cells expressed carbonyl reductase 1 (CBR1) highly and moderately, respectively, the gain of DOX resistance further elevated the CBR1 expression. Additionally, the DOX-elicited cytotoxicity was lowered by overexpression of CBR1 and inversely strengthened by knockdown of the enzyme using small interfering RNA or pretreating with the specific inhibitor quercetin, which also reduced the DOX refractoriness of the two resistant cells. These suggest that CBR1 is a key enzyme responsible for the DOX resistance of gastrointestinal cancer cells and that its inhibitor is useful in the adjuvant therapy. Although CBR1 is known to metabolize DOX to a less toxic anticancer metabolite doxorubicinol, its overexpression in the parental cells hardly show significant reductase activity toward low concentration of DOX. In contrast, the overexpression of CBR1 increased the reductase activity toward an oxidative stress-derived cytotoxic aldehyde 4-oxo-2-nonenal. The sensitivity of the DOX-resistant cells to 4-oxo-2-nonenal was lower than that of the parental cells, and the resistance-elicited hyposensitivity was almost completely ameliorated by addition of the CBR1 inhibitor. Thus, CBR1 may promote development of DOX resistance through detoxification of cytotoxic aldehydes, rather than the drug's metabolism.Key words carbonyl reductase 1; doxorubicin; drug resistance; gastrointestinal cancer cell; quercetin An anthracycline-based antibiotic doxorubicin (DOX) is widely utilized for the treatment of patients not only with solid tumors formed in many organs including breast, lung and stomach, but also with malignant lymphomas. 1) One of the major anticancer actions of DOX is intercalation into the double-stranded DNA and the resultant inhibition of DNA/RNA polymerases.1) In addition, treatment with the drug is known to form the tripartite complex with DNA and topoisomerase-II, ultimately blocking the transcription and replication of DNA. Besides the events essential for protein biosynthesis and cell proliferation, the free radical formation is proposed as another cytolethal mechanism triggered by DOX.1-3) Cellular reductases such as cytochrome P450 reductase 4) and xanthine oxidase 5) catalyze the one-electron reduction of the p-quinone structure in the anthraquinone ring of DOX into a semiquinone radical intermediate, which in turn reacts with molecular oxygen to yield superoxide anion radical. The radical is further converted into a more potent oxidizing agent hydroxyl radical, and thereby oxidatively modifies intracellular components such as nucleic acids, lipids an...

show abstract

Adriamycin stimulated superoxide formation in submitochondrial particles

Cited by 246 publications

References 28 publications

Enzymatic Defenses of the Mouse Heart Against Reactive Oxygen Metabolites

Enzymatic Defenses of the Mouse Heart Against Reactive Oxygen Metabolites

Mitochondrial NADH dehydrogenase‐catalyzed oxygen radical production by adriamycin, and the relative inactivity of 5‐iminodaunorubicin

Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

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