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Protectors against doxorubicin-induced cardiotoxicity: flavonoids.
Cell Biol Toxicol 2007; 23(1):39-47CB

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.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands. a.bast@farmaco.unimaas.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17063376

Citation

Bast, A, et al. "Protectors Against Doxorubicin-induced Cardiotoxicity: Flavonoids." Cell Biology and Toxicology, vol. 23, no. 1, 2007, pp. 39-47.
Bast A, Kaiserová H, den Hartog GJ, et al. Protectors against doxorubicin-induced cardiotoxicity: flavonoids. Cell Biol Toxicol. 2007;23(1):39-47.
Bast, A., Kaiserová, H., den Hartog, G. J., Haenen, G. R., & van der Vijgh, W. J. (2007). Protectors against doxorubicin-induced cardiotoxicity: flavonoids. Cell Biology and Toxicology, 23(1), pp. 39-47.
Bast A, et al. Protectors Against Doxorubicin-induced Cardiotoxicity: Flavonoids. Cell Biol Toxicol. 2007;23(1):39-47. PubMed PMID: 17063376.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protectors against doxorubicin-induced cardiotoxicity: flavonoids. AU - Bast,A, AU - Kaiserová,H, AU - den Hartog,G J M, AU - Haenen,G R M M, AU - van der Vijgh,W J F, Y1 - 2006/10/24/ PY - 2006/06/20/received PY - 2006/08/09/accepted PY - 2006/10/26/pubmed PY - 2007/10/12/medline PY - 2006/10/26/entrez SP - 39 EP - 47 JF - Cell biology and toxicology JO - Cell Biol. Toxicol. VL - 23 IS - 1 N2 - 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. SN - 0742-2091 UR - https://www.unboundmedicine.com/medline/citation/17063376/Protectors_against_doxorubicin_induced_cardiotoxicity:_flavonoids_ L2 - https://doi.org/10.1007/s10565-006-0139-4 DB - PRIME DP - Unbound Medicine ER -