Key result
MonoHER effectively suppressed doxorubicin-induced apoptosis in cardiac and endothelial cells by 13- to 15-fold through inhibition of both caspase-dependent and -independent pathways, with less protective effect on ovarian cancer cells.
Why the study?
Does monoHER prevent doxorubicin-induced apoptosis in cardiac, endothelial, and tumor cells?
Does monoHER prevent doxorubicin-induced apoptosis in cardiac, endothelial, and tumor cells?
MonoHER protects against doxorubicin-induced apoptosis in cardiac and endothelial cells by suppressing both caspase-dependent and -independent pathways, though high concentrations may also protect tumor cells.
May support selective DOX cardioprotection without antitumor interference; leaves open clinical translation from neonatal rat apoptosis data.
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.
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Bruynzeel et al. (2007) studied Doxorubicin-induced apoptosis and cardiotoxicity. monoHER (7-Monohydroxyethylrutoside) vs. Doxorubicin alone was evaluated on DOX-induced apoptosis (sub-G1 cell fraction). MonoHER effectively suppressed doxorubicin-induced apoptosis in cardiac and endothelial cells by 13- to 15-fold through inhibition of both caspase-dependent and -independent pathways, with less protective effect on ovarian cancer cells.
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