title: Desferrioxamine attenuates doxorubicin-induced acute cardiotoxicity through TFG-β/Smad p53 pathway in rat model.
abstract: Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.
authors.affiliation: Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. shabanah@ksu.edu.sa
authors.forename: Othman A
authors.initials: OA
authors.lastname: Al-Shabanah
authors.forename: Abdulaziz M
authors.initials: AM
authors.lastname: Aleisa
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Hafez
authors.forename: Salim S
authors.initials: SS
authors.lastname: Al-Rejaie
authors.forename: Abdulaziz A
authors.initials: AA
authors.lastname: Al-Yahya
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Bakheet
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Al-Harbi
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Sayed-Ahmed
mesh_terms: D000818:Animals; D054715:Cardiotoxins; D003676:Deferoxamine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004317:Doxorubicin; D005786:Gene Expression Regulation / Q000187:drug effects; D006331:Heart Diseases / Q000097:blood / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control*; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D054715:Cardiotoxins; D007527:Isoenzymes; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D003676:Deferoxamine