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/m2 of 7-monohydroxyethylrutoside is feasible and is safe to be investigated as protection against doxorubicin-induced cardiotoxicity.
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Abbreviations
- ABAP:
-
azobisamidinopropane
- DMSO:
-
dimethyl sulfoxide
- DTNB:
-
5,5′-dithiobis(2-nitrobenzoic acid)
- GSH:
-
(reduced) glutathione
- HUVECs:
-
human umbilical cord vascular endothelial cells
- i.p.:
-
intraperitoneal(ly)
- i.v.:
-
intravenous(ly)
- LDH:
-
lactate dehydrogenase
- VCAM:
-
vascular cell adhesion molecule
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Bast, A., Kaiserová, H., den Hartog, G.J.M. et al. Protectors against doxorubicin-induced cardiotoxicity: Flavonoids. Cell Biol Toxicol 23, 39–47 (2007). https://doi.org/10.1007/s10565-006-0139-4
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DOI: https://doi.org/10.1007/s10565-006-0139-4