METHOD FOUND TO PREVENT ANTHRACYCLINE (doxorubicin) CARDIOTOXICITY (in rats)

[Lani]

(OOPS, sorry it was mice)

Cannabinoid Receptor Inhibitors May Prevent Doxorubicin Toxicity


NW YORK (Reuters Health) Aug 09 - The severe cardiotoxicity that can limit the use of the antitumor agent, doxorubicin, appears to be minimized with antagonists to the cannabinoid-1 (CB-1) receptor, according to the results of in vivo and in vitro research.

The findings are reported in the August 7th issue of the Journal of the American College of Cardiology.

Dr. Partha Mukhopadhyay of the National Institutes of Health in Bethesda, Maryland, and colleagues analyzed the effects of CB-1 receptor inhibition in animal models of doxorubicin cardiotoxicity.

The investigators measured left ventricular function, apoptosis markers, CB-1 and CB-2 receptor expression and endocannabinoid levels at baseline and again after pretreatment with the CB-1 antagonists rimonabant and AM281 or vehicle in male mice.

Five days after a single 20 mg/kg intraperitoneal injection of doxorubicin in mice, the investigators saw that a number of markers of cardiac function were significantly less depressed in the two groups given the CB-1 antagonists compared with the control animals given the vehicle injection.

Left ventricular systolic pressure, stroke work, ejection fraction, cardiac output and measures of contractility were all better in animals on CB-1 inhibitors compared with control animals.

Myocardial levels of the endocannabinoid anandamide, but not CB-1 or CB-2 receptor expression, were elevated with doxorubicin treatment.

Cardiac dysfunction was significantly attenuated in animals treated with rimonabant or AM281 compared with vehicle. The CB-1 antagonists also markedly reduced doxorubicin-induced myocardial apoptosis.

In vitro studies showed that a CB-1 antagonist, but not a CB-2 antagonist or agonists to CB-1 and CB-2 receptors prevented cardiomyocyte apoptosis and increased cell viability.

"The observed protective effect of CB-1 antagonists and the doxorubicin-induced increase in myocardial anandamide content may, therefore, suggest that doxorubicin-induced cardiotoxicity is associated with and mediated, at least in part, by activation of the endocannabinoid system," Dr. Mukhopadhyay and colleagues propose.

"These data provide support for the role of the endocannabinoid system as a potentially novel target for the protection against doxorubicin cardiotoxicity. Unfortunately, the present study does not provide sufficient data to fully understand the mechanism for the beneficial effects of CB1 inhibition," editorialists Drs. Giovanni Fajardo and Daniel Bernstein from Stanford University, California, comment.

Additional studies will be needed to see if CB-1 receptor inhibition effects doxorubicin's anti-tumor activity.

The physicians add that "a better understanding of the role of this novel receptor system in mediating cardioprotection may have benefits that extend beyond doxorubicin cardiotoxicity to other forms of cardiac injury."

J Am Coll Cardiol 2007;50:528-539.