title: 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 micro M monoHER. Resting (confluent) HUVECs were incubated with (0.5-25 micro M) 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)=60.0+/-20.8 nM) than resting cells (LC(50)=4.0+/-0.3 micro M). Doxorubicin also increased the adhesion of neutrophils reaching a plateau value at a doxorubicin concentration of > or =0.4 micro M (P=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 (< or =25 micro M, P<0.0015). 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.
authors.affiliation: Department of Medical Oncology, Free University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. m.abulhassan@vumc.nl
authors.forename: M A I
authors.initials: MA
authors.lastname: Abou El Hassan
authors.forename: H M W
authors.initials: HM
authors.lastname: Verheul
authors.forename: A S
authors.initials: AS
authors.lastname: Jorna
authors.forename: C
authors.initials: C
authors.lastname: Schalkwijk
authors.forename: J
authors.initials: J
authors.lastname: van Bezu
authors.forename: W J F
authors.initials: WJ
authors.lastname: van der Vijgh
authors.forename: A
authors.initials: A
authors.lastname: Bast
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000166:cytology; D006896:Hydroxyethylrutoside / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced* / Q000517:prevention & control*; D009504:Neutrophils; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D006896:Hydroxyethylrutoside; D004317:Doxorubicin