Analyses of the Molecular Mechanism of Adriamycin-Induced Cardiotoxicity

Gille, Lars; Nohl, Hans

doi:10.1016/s0891-5849(97)00025-7

Cited by 188 publications

(136 citation statements)

References 23 publications

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“…One of them is the intracellular production of free oxygen radicals, which had been held responsible for the cumulative cardiotoxicity of anthracyclines. [27][28][29] Although we did not examine the nature of DNA damage in this project (eg single-or double-strand breaks, protein associated or not, etc), the composition of DNA damage induced by the different drugs as displayed in Figure 2 are distinct. Classical anthracyclines, such as daunorubicin, induce both topo II associated DNA damage and damage due to free oxygen radicals.…”

Section: Discussionmentioning

confidence: 99%

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Gieseler¹,

Bauer

Nuessler³

et al. 1999

Leukemia

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We examined the cellular effects of topo II inhibitors in two human myeloid cell lines, HL-60 and KG-1 cells, with the purpose of finding molecular markers for the sensitivity of leukemia cells to topo II inhibitors. These cell lines are widely used, well characterized and they differ in their sensitivities to topo II inhibitors. Despite the fact that HL-60 cells are p53-negative, they are much more sensitive than KG-1 cells. Three different topo II inhibitors with distinct molecular ways of action have been used. Daunorubicin and aclarubicin are DNA intercalators that secondarily interact with topo II; etoposide, on the other hand, directly binds to the enzyme. In contrast to daunorubicin, which induces protein-associated DNA double-strand breaks due to the blockage of topo II action, aclarubicin inhibits the access of DNA by topo II. No correlation could be established between the drug-induced DNA damage and apoptosis. In fact, the amount and pattern of DNA damage examined with the 'comet assay' was characteristic for each drug in both cell lines. The DNA binding of daunorubicin was slightly higher in HL-60 cells, but there was no notable variance between the cell lines for aclarubicin. The most striking difference could be found for the nuclear topo II activity, which was about half in KG-1 cells and, additionally, less than 1% of the nuclear topo II activity was bound to the DNA in KG-1 cells when compared to HL-60 cells. This fraction of topo II interacts with the inhibitors; subsequently these findings might well explain the variance in the cellular sensitivity. Additional factors are alterations of the apoptotic pathways, eg loss of p53 in HL-60 cells. Although we found no differences in the quantity of DNA damage between the cell lines after drug treatment, the quality of DNA damage appeared to be distinct for each topo II inhibitor. The morphological appearance of the comet tails after treatment was characteristic for each drug. Further studies are necessary to decide whether these in vitro data are compatible with the clinical situation.

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Section: Discussionmentioning

confidence: 99%

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Gieseler¹,

Bauer

Nuessler³

et al. 1999

Leukemia

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“…DOX is enzymatically reduced to the DOX semiquinone radical. This semiquinone radical directly transfers its electron to molecular oxygen, generating a superoxide and hydrogen peroxide [3] . Because of free radical plays important roles in DOX-induce cardiotoxicity, it is logical to consider antioxidants as primary potential therapeutic agent to prevent such toxic effect.…”

Section: Doxorubicinmentioning

confidence: 99%

Sesame Oil as a Protective Agent Against Doxorubicin Induced Cardio Toxicity in Rat

Shad¹,

Al-Salam²,

Hamza³

2007

American J. of Pharmacology and Toxicology

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Abstract:The therapeutic value of doxorubicin (DXO) as anticancer antibiotic is limited by its cardiotoxicity. This study aimed to investigate the protective effect of sesame oil against DXO-induced cardiotoxicity and oxidative stress. The administration of DXO (20 mg/kg) to Wister male rats, increased serum aspartate aminotransferase and creatine kinase activities (as cardiotoxicity indices) as well as cardiac malondialdehyde and protein carbonyl contents and catalase activity (as markers of oxidative stress). The cardiotoxicity damage in DOX treated rats was accompanied by histo pathological changes such as necrosis and apoptosis in cardiac tissues. These biochemical and histological disturbances were effectively attenuated on pretreatment with sesame oil (5ml/kg). These data suggest that sesame oil may be a suitable cardio protector during DOX treatment.

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“…Although Dox-induced myocardial dysfunction is multifactorial, the putative main mechanism for Dox-induced cardiotoxicity is the production of free radicals during its intracellular metabolism. Free radicals cause diverse oxidative damage to critical cellular components and membranes in heart tissues [6,7,17]. Moreover, the heart is very sensitive to oxidative stress owing to its highly oxidative metabolism, and it has a lower level of antioxidant defense systems than the liver [5].…”

Section: Introductionmentioning

confidence: 99%

Schisandra fructus extract ameliorates doxorubicin-induce cytotoxicity in cardiomyocytes: altered gene expression for detoxification enzymes

et al. 2007

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The effect of Schisandra fructus extract (SFE) on doxorubicin (Dox)-induced cardiotoxicity was investigated in H9c2 cardiomyocytes. Dox, which is an antineoplastic drug known to induce cardiomyopathy possibly through production of reactive oxygen species, induced significant cytotoxicity, intracellular reactive oxygen species (ROS), and lipid peroxidation. SFE treatment significantly increased cell survival up to 25%, inhibited intracellular ROS production in a time-and dosedependent manner, and inhibited lipid peroxidation induced by Dox. In addition, SFE treatment induced expression of cellular glutathione S-transferases (GSTs), which function in the detoxification of xenobiotics, and endogenous toxicants including lipid peoxides. Analyses of 31,100 genes using Affymetrix cDNA microarrays showed that SFE treatment up-regulated expression of genes involved in glutathione metabolism and detoxification [GST theta 1, mu 1, and alpha type 2, heme oxygenase 1 (HO-1), and microsomal epoxide hydrolase (mEH)] and energy metabolism [carnitine palmitoyltransferase-1 (CPT-1), transaldolase, and transketolase]. These data indicated that SFE might increase the resistance to cardiac cell injury by Dox, at least partly, together with altering gene expression, especially induction of phase II detoxification enzymes.

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Analyses of the Molecular Mechanism of Adriamycin-Induced Cardiotoxicity

Cited by 188 publications

References 23 publications

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Molecular effects of topoisomerase II inhibitors in AML cell lines: correlation of apoptosis with topoisomerase II activity but not with DNA damage

Sesame Oil as a Protective Agent Against Doxorubicin Induced Cardio Toxicity in Rat

Schisandra fructus extract ameliorates doxorubicin-induce cytotoxicity in cardiomyocytes: altered gene expression for detoxification enzymes

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