Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice

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 fluvastatintreated (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, À29%; dp/dtmax, À45%; cardiac output, À68%; 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 A 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 antiinflammatory effects. [Cancer Res 2009;69(2):695-9]

Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro

“…DOX-induced increased superoxide/ROS generation is also an early event in vivo, as demonstrated by numerous studies (e.g., Refs. 6, 16, and 43), whereas more significant histological damage, cell death, and cardiac dysfunction peak only later (when DOX is no longer present in the circulation/myocardium), concomitantly with the increased myocardial NT formation (43,53,65) (Supplemental Figs. 1 and 2).…”

ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

“…37 Pretreatment with statins can attenuate doxorubicin-induced cardiotoxicity via anti-inflammatory effects. 38 Olson et al reported a novel anthracycline analog, DIDOX, which was structurally modified from doxorubicin. DIDOX inhibits the production of the pro-inflammatory cytokines, TNFα and IL-2.…”

Exercise Preconditioning Provides Long-Term Protection Against Early Chronic Doxorubicin Cardiotoxicity

“…Studies examining the effectiveness of these interventions, however, typically investigate only acute cardiotoxicity. [8][9][10][11] Such interventions targeted against acute cardiotoxicity include the use of iron chelators, 12 antioxidants, 13,14 statins, 15 and amino acid supplementation. 16,17 These acute DOX cardiotoxicity studies have limited clinical application, however, since chronic forms of DOX cardiotoxicity can 392577I CT10110.1177/153473541039257 7Hydock et alIntegrative Cancer Therapies 1 University of Northern Colorado, Greeley, CO, USA manifest in the absence of severe acute cardiotoxicity.…”