title: Carfilzomib-induced cardiotoxicity mitigated by dexrazoxane through inhibition of hypertrophic gene expression and oxidative stress in rats.
abstract: Carfilzomib (CFZ) is an inhibitor of proteasome that is generally used in the treatment of multiple myeloma but due to its cardiotoxicity clinical use may be limited. Dexrazoxane (DZR), an inhibitor of topoisomerase-II, prevents cardiac damage by reducing the formation of reactive oxygen species and hypertrophic gene expression. This study evaluated the protective effect of DZR on CFZ-induced cardiotoxicity. Thirty-two male Albino rats were randomly divided into four groups (n = 8). Group I received DMSO, Group II received CFZ (4 mg/kg, intraperitoneally [i.p.]) twice weekly up to day 16, Group III received DZR (20 mg/kg, i.p.) for 16 days and CFZ twice weekly for 16, Group IV received DZR (40 mg/kg, i.p.) for 16 days and CFZ twice weekly for 16. CFZ-induced cardiotoxicity was assessed by hematological, biochemical, mRNA expression, oxidative stress and histopathological studies. CFZ-induced significant changes have been observed in blood parameters including red blood cells, white blood cells, hemoglobin and hematocrit concentrations which were associated with increase in cardiac enzymes markers like creatine kinase (CK), CK-MB and lactate dehydrogenase. Treatment with DZR reversed the hematological statistics and the biochemical markers of CFZ-induced cardiotoxicity. Furthermore, DZR also attenuated the effects of CFZ-induced toxic effect on redox markers such as malondialdehyde and reduced glutathione. Above findings were further confirmed by beta-myosin heavy chain (β-MHC) and alpha-MHC (α-MHC) gene expression. Histopathological reports suggested that DZR ameliorates CFZ-induced changes in cardiac cellular architecture in rats. These results confirm that DZR protects heart from CFZ-induced cardiotoxicity.
authors.affiliation: a Department of Pharmacology and Toxicology , College of Pharmacy, King Saud University , Riyadh , KSA.
authors.forename: Naif O
authors.initials: NO
authors.lastname: Al-Harbi
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D066126:Cardiotoxicity; D064730:Dexrazoxane / Q000008:administration & dosage / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects*; D008297:Male; D009842:Oligopeptides / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: D002316:Cardiotonic Agents; D009842:Oligopeptides; D064730:Dexrazoxane; C524865:carfilzomib; D024723:Ventricular Myosins
keywords: cardiotoxicity; carfilzomib; dexrazoxane; proteasome inhibitor; α-MHC; β-MHC