The new cardioprotector Monohydroxyethylrutoside protects against doxorubicin-induced inflammatory effects in vitro

Abstract

Besides its cardiotoxic effect, doxorubicin also elicits inflammatory effects in vivo. 7-Monohydroxyethylrutoside (monoHER) has recently been used as a protector against doxorubicin-induced cardiotoxicity in vivo. It is not known yet whether monoHER can also protect against doxorubicin-induced inflammatory effects. The aim of the present study was (1) to illustrate the inflammatory effects of doxorubicin in vitro and (2) to evaluate a possibly protective effect of monoHER. In order to demonstrate the inflammatory effects of doxorubicin and the possible protection of monoHER, proliferating human umbilical cord vascular endothelial cells (HUVECs) were incubated with different concentrations of doxorubicin ranging from 12.5 to 600 nM with(out) 200 mM monoHER. Resting (confluent) HUVECs were incubated with (0.5 -25 mM) doxorubicin with(out) monoHER (0.2 -1.2 mM) and the viability of endothelial cells and their propensity to adhere to neutrophils were measured 24 h after treatment. The localisation of adhered neutrophils was determined with immunofluorescence microscopy. To further characterise the mechanism of doxorubicin-induced neutrophil adhesion, the expression of the HUVECs surface adhesion molecules was determined after doxorubicin treatment. Doxorubicin decreased the viability and proliferation capacity of HUVECs in a concentration-dependent manner. The proliferating HUVECs were much more sensitive to doxorubicin (IC 50 ¼ 60.0720.8 nM) than resting cells (LC 50 ¼ 4.070.3 mM). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of X0.4mM (P ¼ 0.0113). The induced neutrophil adhesion was accompanied by overexpression of VCAM and E-selectin but not ICAM. Although monoHER did not reverse the effect of doxorubicin on the proliferation of endothelial cells, it significantly protected resting HUVECs against the cytotoxic effect of doxorubicin (p25 mM, Po0.0015). In addition, monoHER completely protected against the stimulatory effect of doxorubicin on neutrophil adhesion, and inhibited the doxorubin-induced expression of VCAM and E-selectin on the surface of treated HUVECs. This study illustrates that monoHER, which protects against doxorubicin's cardiotoxic effect, can also protect against doxorubicin-induced inflammatory effects. These data prompt further investigation about the possible link between doxorubicin-induced inflammatory effects and its cardiotoxicity in vivo.

Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

“…Several studies showed that inflammatory effects are directly and indirectly caused by treatment with DOX. In vitro it was shown that DOX directly induced neutrophil adhesion of vascular endothelial cells via the overexpression of VCAM and E-selectin (Abou El Hassan et al, 2003), whereas results of another study suggest that treatment with DOX produced marked inflammatory changes in heart tissue, liver and kidneys (Deepa and Varalakshmi, 2005). Results of our study confirm the contribution of inflammation in DOX-induced cardiotoxicity, because anti-inflammatory agents can at least, in part, reduce DOX-induced cardiotoxicity.…”

“…Doxorubicin elevates NF-kB (Baeuerle, 1991;Read et al, 1994;Goto et al, 1999;Hou et al, 2005;Deepa and Varalakshmi, 2006) and the adhesion molecules VCAM-1 and E-selectin (Abou El Hassan et al, 2003). In vitro data showed that DOX affected both the viability and neutrophil adhesion of endothelial cells with clinically achievable concentrations (Abou El Hassan et al, 2003). These inflammatory effects may play a role in DOX-induced cardiotoxicity and results of some studies support these indications (Inchiosa Jr and Smith, 1990;Chen et al, 2005;Hou et al, 2005).…”

“…In a recent study, was found that CML positivity colocalised with E-selectinpositive endothelial cells in the heart (Baidoshvili et al, 2006). Earlier it was demonstrated that DOX induced neutrophil adhesion that was mediated via overexpression of E-selectin (Abou El Hassan et al, 2003). Therefore, it is tempting to speculate that CML is derived from these pathways and could play a role in DOXinduced vascular endothelial injury and subsequent cardiotoxicity.…”

“…Doxorubicin elevates NF-kB (Baeuerle, 1991;Read et al, 1994;Goto et al, 1999;Hou et al, 2005;Deepa and Varalakshmi, 2006) and the adhesion molecules VCAM-1 and E-selectin (Abou El Hassan et al, 2003). In vitro data showed that DOX affected both the viability and neutrophil adhesion of endothelial cells with clinically achievable concentrations (Abou El Hassan et al, 2003).…”

“…In vitro, we have also shown that monoHER protects against DOX-induced inflammatory effects (Abou El Hassan et al, 2003). Therefore, the effect of monoHER on DOXinduced CML increase was also investigated in the in vivo mouse model.…”