Desferrioxamine Attenuates Doxorubicin‐Induced Acute Cardiotoxicity Through TGF‐β/Smad P53 pathway

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic with broad spectrum antitumour activity against different types of human malignancies. Unfortunately, the optimal clinical usefulness of DOX is usually associated with both acute and chronic cardiotoxicity. Interaction of DOX with iron with the consequent generation of reactive oxygen species (ROS) is a major player in DOX‐induced cardiomyopathy. Accordingly, this study has been initiated to investigate, on gene expression level, the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX‐induced cardiotoxicity in rat. Male Wistar albino rats were divided into four groups. Group 1 was injected intra‐peritoneally (I.P.) with normal saline and served as control. Group 2 (DOX group) was injected with a single dose of DOX (15 mg/kg, I.P.). Rats in group 3 were given a single dose of DXF (250 mg/kg, I.P.). Animals in group 4 were injected with DFX (250 mg/kg) 30 min prior to a single dose of DOX (15 mg/kg, I.P.). Twenty four hours later, animals were sacrificed and hearts were isolated for studying mRNA expression of genes involved in TGF‐β/Smad P53 pathway using Real‐Time PCR. A single dose of DOX significantly increased mRNA expression of TGF‐β, Smad2, Smad4, CDKN2A and P53 and significantly decreased the expression of Samd7 and Mdm2 gene expression levels. Administration of DXF prior to DOX‐resulted in complete reversal of DOX‐induced alteration in the studied genes expression to normal levels. The protective effect of DXF was showed in restoring the normal levels of the cardiac enzymes and isoenzymes after treatment. Data from this study study suggest that: (1) DOX induces its acute cardiotoxicity secondary to increasing the expression of TGF‐β/Smad pathway. (2) DOX increases apoptosis through up‐regulation of CDKN2A and P53 and down‐regulation of Mdm2 gene expression. (3) The preventive effect of DXF against DOX‐induced cardiotoxicity is mediated via the TGF‐β1/Smad pathway.