title: Flavaglines alleviate doxorubicin cardiotoxicity: implication of Hsp27.
abstract: 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.
  
  
  RESULTS
  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
  These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induced cardiac toxicity.
authors: Therapeutic Innovation Laboratory, UMR7200, CNRS/Université de Strasbourg, Illkirch, France.
authors: Yohann
authors: Y
authors: Bernard
authors: Nigel
authors: N
authors: Ribeiro
authors: Frédéric
authors: F
authors: Thuaud
authors: Gülen
authors: G
authors: Türkeri
authors: Ronan
authors: R
authors: Dirr
authors: Mounia
authors: M
authors: Boulberdaa
authors: Canan G
authors: CG
authors: Nebigil
authors: Laurent
authors: L
authors: Désaubry
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D019610:Cytoprotection / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects*; D005355:Fibrosis; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D001572:Benzofurans; D002316:Cardiotonic Agents; D016895:Culture Media, Serum-Free; D055551:HSP27 Heat-Shock Proteins; D004317:Doxorubicin