Doxorubicin (DOX) is an antitumour agent for different types of
cancer, but the dose-related
cardiotoxicity limits its clinical use. To prevent this side effect we have developed the
flavonoid monohydroxyethylrutoside (
monoHER), a promising
protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of
monoHER, we investigated whether
monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the
ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by
monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOX-induced apoptosis. Experiments with the
caspase-inhibitor
zVAD-fmk showed that DOX-induced apoptosis was
caspase-dependent in HUVECs and A2780 cells, whereas
caspase-independent mechanisms seem to be important in NeRCaMs.
MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of
caspase-9 and -3 cleavage. Thus,
monoHER acts by suppressing the activation of molecular mechanisms that mediate either
caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of
monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.