Flavaglines alleviate doxorubicin cardiotoxicity: implication of Hsp27.
Fiche publication
Date publication
janvier 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent, Dr NEBIGIL-DESAUBRY Canan
Tous les auteurs :
Bernard Y, Ribeiro N, Thuaud F, Turkeri G, Dirr R, Boulberdaa M, Nebigil CG, Desaubry L
Lien Pubmed
Résumé
BACKGROUND: Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicin-induced cardiotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50% decrease of mortality. CONCLUSIONS/SIGNIFICANCE: These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induced cardiac toxicity.
Référence
PLoS One. 2011;6(10):e25302