Protectors against doxorubicin-induced cardiotoxicity: Flavonoids

Abstract

Doxorubicin is a widely used anthracycline anticancer agent. Its use may cause cardiomyopathy: in fact, the development of cumulative dose-related cardiotoxicity forms the major limitation of clinical doxorubicin use. We therefore searched for protective agents that combine iron-chelating and oxygen radical-scavenging properties. Moreover, any novel protector should not interfere with the cytostatic activity of doxorubicin. After extensive in vitro screening we found that flavonoids could serve this purpose. In particular 7-monohydroxyethylrutoside almost completely protected against the negative inotropic action of doxorubicin in the electrically paced mouse left atrium model. In vivo it gave full protection at 500 mg/kg intraperitoneally against the doxorubicin-induced ST-interval lengthening in the ECG. Moreover, this protector did not influence the antitumor effect of doxorubicin either in vitro using the human ovarian cell lines A2780 and OVCAR-3 and the human breast cancer cell line MCF-7 or in vivo in A2780 and OVCAR-3 subcutaneous xenografts in nude mice. Comparison of various iron chelators suggest that iron, in contrast to the general assumption, might not play a crucial role in the oxidative stress-induced toxicity of doxorubicin. Moreover, incubation of vascular endothelial cells with doxorubicin produced overexpression of adhesion molecules, which could be inhibited by 7-monohydroxyethylrutoside. From a study in human volunteers, we conclude that an intravenous dose of 1500 mg/m(2) of 7-monohydroxyethylrutoside is feasible and is safe to be investigated as protection against doxorubicin-induced cardiotoxicity.

Activation of Nuclear Factor-κB Pathway by Simvastatin and RhoA Silencing Increases Doxorubicin Cytotoxicity in Human Colon Cancer HT29 Cells

“…As for many other chemotherapeutic agents, the clinical use of doxorubicin is hampered by several side effects, including cardiotoxicity (Bast et al, 2007), which is the major limitation to doxorubicin use and impairs the clinical response and the survival of patients (Bryant et al, 2007). To limit the myocardial damage, less cardiotoxic doxorubicin derivatives (Batist et al, 2001) or the coadministration with cardioprotectors, such as dexrazoxane, coenzyme Q10 (Batist et al, 2001), and flavonoids (Bast et al, 2007), has been proposed without obtaining satisfying results.…”

Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents

“…One promising approach to solve this problem is the application of cochemotherapeutic agent in cancer therapy (Brenner, 2002). Co-chemotherapy may increase chemotherapeutic agents' efficacy, allowing the use of lower dosage of chemotherapeutic agent, resulting in the decrease of toxicity on normal tissues (Bastl et al, 2007). Increasing efficacy may be obtained by combining agents with established chemotherapeutic agents having additive or synergistic effect, while decreasing the toxicity may be achieved by the use of agents possessing immunomodulatory effect (Olson et al, 2007).…”

Protective effects of naringenin-7-O-glucoside on doxorubicin-induced apoptosis in H9C2 cells

“…Flavonoids, a group of polyphenols, possess potent cardioprotective efficacy and significantly reduce the risk of cardiovascular disease (Bast et al, 2007;Du et al, 2007;Peluso, 2006;Huxley and Neil, 2003). Some research groups have reported that flavonoids exhibit protective effects against cardiomyopathy and cardiomyocyte apoptosis induced by doxorubicin (Bagchi et al, 2003;Hüsken et al, 1995).…”