Flavaglines alleviate doxorubicin cardiotoxicity: implication of Hsp27

• Published in: PloS one 2011-10, Vol.6 (10), p.e25302
• Main Authors: Bernard, Yohann, Ribeiro, Nigel, Thuaud, Frédéric, Türkeri, Gülen, Dirr, Ronan, Boulberdaa, Mounia, Nebigil, Canan G, Désaubry, Laurent
• Format: Article
• Language: English
• Subjects: Animals; Annexin V; Anthracyclines; Apoptosis; Apoptosis - drug effects; Benzofurans - chemistry; Benzofurans - pharmacology; Biology; Cancer; Cancer treatment; Cardiology and cardiovascular system; Cardiomyocytes; Cardiomyopathy; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacology; Cardiotoxicity; Caspase; Caspase-3; Cell culture; Culture Media, Serum-Free; Cytoprotection - drug effects; Doxorubicin; Doxorubicin - adverse effects; Fibrosis; Genes; Glucose; Heart; Heart diseases; Heart failure; Heat shock proteins; HSP27 Heat-Shock Proteins - metabolism; Hsp27 protein; Human health and pathology; Laboratories; Life Sciences; Lymphoma; Male; Medicine; Mice; Mice, Inbred BALB C; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Neuroprotection; Oxidative stress; Phosphorylation; Phosphorylation - drug effects; Rodents; Toxicity; Viability
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025302

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. 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. These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induced cardiac toxicity.