Back to Search
Start Over
Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice.
- Source :
-
Cancer research [Cancer Res] 2009 Jan 15; Vol. 69 (2), pp. 695-9. - Publication Year :
- 2009
-
Abstract
- Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, -29%; dp/dtmax, -45%; cardiac output, -68%; P < 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor alpha and Bax (P < 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P < 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects.
- Subjects :
- Animals
Apoptosis drug effects
Cardiomyopathies chemically induced
Cardiomyopathies metabolism
Cardiomyopathies physiopathology
Drug Interactions
Fluvastatin
Isoenzymes
Lipid Peroxidation drug effects
Mice
Mice, Inbred C57BL
Oxidative Stress drug effects
Random Allocation
Superoxide Dismutase biosynthesis
Superoxide Dismutase metabolism
Tumor Necrosis Factor-alpha biosynthesis
Ventricular Function, Left drug effects
Antibiotics, Antineoplastic toxicity
Cardiomyopathies prevention & control
Doxorubicin toxicity
Fatty Acids, Monounsaturated pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
Indoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 69
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 19147586
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-08-3076