Monohydroxyethylrutoside as protector against chronic doxorubicin‐induced cardiotoxicity

Abstract

The clinical use of the antitumour agent, doxorubicin, is largely limited by the development of a cumulative dose‐related cardiotoxicity. This toxicity is generally believed to be caused by the formation of oxygen free radicals. In earlier studies it was established that flavonoids, naturally occurring antioxidants, can provide some degree of protection. In this study we investigated whether 7‐monohydroxyethylrutoside (monoHER), a powerful antioxidative flavonoid with extremely low toxicity, can provide protection to an extent comparable to the clinically successful Cardioxane (ICRF‐187). Balb/c mice of 20–25 g were equipped i.p. with a telemeter to measure ECG. They were given 6 i.v. doses of doxorubicin (4 mg kg −1) at weekly intervals. ICRF‐187 (50 mg kg−1) or monoHER (500 mg kg−1) were administered i.p. 1 h before doxorubicin administration. In the 2 monoHER groups the treatment continued with either 1 or 4 additional injections per week. A saline and monoHER treated group served as controls. After these 6 weeks, they were observed for another 2 weeks. At the end of this study (week 8) the ST interval had increased by 16.7 ±2.7 ms (mean ± s.e.mean) in doxorubicin‐treated mice. At that time, the ST interval had increased by only 1.8 ±0.9 ms in ICRF‐187 co‐mediated mice and in monoHER co‐medicated mice by only 1.7 ±0.8 and 5.1 ± 1.7 ms (5‐ and 2‐day schedule, respectively, all P< 0.001 relative to doxorubicin and not significantly different from control). The ECG of the control animals did not change during the entire study. The QRS complex did not change in either group. It can be concluded that monoHER protects against doxorubicin‐induced cardiotoxicity and merits further evaluation in this respect.

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

“…Interestingly, the potent ROS scavenger monoHER, which is presently in a clinical phase II study, showed a strong protection against the cardiotoxic effects of DOX without modulating its antitumour effects both in vivo and in vitro (van Acker et al, 1997;van Acker et al, 2000;Abou El Hassan et al, 2003a, d). The antiapoptotic role played by monoHER and the contribution to its selective protection is not studied yet.…”

“…In our studies the scavenging activity of monoHER was measured by determining the inhibition of ferricytochrome c reduction and the inhibition of oxygen consumption, showing an inhibition of 91 and 70%, respectively (van Acker et al, 1993). Because of these favourable properties, monoHER was tested as a protectant against DOX-induced cardiac damage in in vivo models and appeared a potent protector against DOX-induced cardiotoxicity without influencing its antitumour effects (van Acker et al, 1997(van Acker et al, , 2000.…”

Effect of Flavonoids on Daunorubicin‐induced Toxicity in H9c2 Cardiomyoblasts

“…Although the exact molecular mechanisms of cardiotoxicity are not well established, oxidative mechanisms involving daunorubicin-induced reactive oxygen species production have been proposed (Zucchi and Danesi, 2003). The heart is particularly vulnerable to damage induced by ROS because protective enzymes such as superoxide dismutase and catalase are present at a lower level there than in other tissues of the body (Van Acker et al, 2000).…”

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

“…In the past, we have shown the cardioprotective properties of the antioxidant 7-monohydroxyethylrutoside (monoHER) against DOX-induced cardiotoxicity in mouse (Van Acker et al, 1997;Van Acker et al, 2000). In vitro, we have also shown that monoHER protects against DOX-induced inflammatory effects (Abou El Hassan et al, 2003).…”