Role of hypoxia-inducible factors in the dexrazoxane-mediated protection of cardiomyocytes from doxorubicin-induced toxicity
Authors: S Recalcati
L Tacchini
R D Spagnuolo
G Cairo
Journal: British journal of pharmacology (2011)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Iron; doxorubicin; dexrazoxane; cardiotoxicity; hypoxia-inducible factors (HIF)
Affiliations: Department of Human Morphology and Biomedical Sciences 'Città Studi', University of Milan, Milano, Italy.

Abstract:  Background and purpose: Iron aggravates the cardiotoxicity of doxorubicin, a widely used anticancer anthracycline, and the iron chelator dexrazoxane is the only agent protecting against doxorubicin cardiotoxicity; however, the mechanisms underlying the role of iron in doxorubicin-mediated cardiotoxicity and the protective role of dexrazoxane remain to be established. As iron is required for the degradation of hypoxia-inducible factors (HIF), which control the expression of antiapoptotic and protective genes, we tested the hypothesis that dexrazoxane-dependent HIF activation may mediate the cardioprotective effect of dexrazoxane. Experimental approach: Cell death, protein levels (by immunoblotting) and HIF-mediated transcription (using reporter constructs) were evaluated in the rat H9c2 cardiomyocyte cell line exposed to low doses of doxorubicin with or without dexrazoxane pretreatment. HIF levels were genetically manipulated by transfecting dominant-negative mutants or short hairpin RNA. Key results: Treatment with dexrazoxane induced HIF-1α and HIF-2α protein levels and transactivation capacity in H9c2 cells. It also prevented the induction of cell death and apoptosis by exposure of H9c2 cells to clinically relevant concentrations of doxorubicin. Suppression of HIF activity strongly reduced the protective effect of dexrazoxane. Conversely, HIF-1α overexpression protected against doxorubicin-mediated cell death and apoptosis also in cells not exposed to the chelator. Exposure to dexrazoxane increased the expression of the HIF-regulated, antiapoptotic proteins survivin, Mcl1 and haem oxygenase. Conclusions and implications: Our results showing HIF-dependent prevention of doxorubicin toxicity in dexrazoxane-treated H9c2 cardiomyocytes suggest that HIF activation may be a mechanism contributing to the protective effect of dexrazoxane against anthracycline cardiotoxicity. 

Retracted: Yes

PubPeer comments:
 Comparing Fig 1a *[right]* against *[left]* Fig 1D from [De Ponti et al (2007)] : ![file] Surprisingly similar after a horizontal flip. , 
 Fig 3A *[below]*, compared with *[above]* Fig 2B from [Tacchini et al (2007)] : ![file] , 
 Retracted [May 20 2020] :  The above article, published online on January 14, 2011, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal s Editoru2010inu2010Chief, Professor Amrita Ahluwalia, the British Pharmacological Society, and John Wiley Sons Ltd. The retraction has been agreed due to the duplication of Figures 1A and 3A, which overlap with figures appearing in another article published by the authors in the Journal of Leukocyte Biology in 2008. The authors state that due to the time elapsed, they are unable to provide evidence of the original data. ,