title: Apremilast reversed carfilzomib-induced cardiotoxicity through inhibition of oxidative stress, NF-κB and MAPK signaling in rats.
abstract: Carfilzomib (CFZ), is a potent, selective second generation proteasome inhibitor, used for the treatment of multiple myeloma. The aim of the present study was to investigate the possible protective effect of apremilast (AP) on the CFZ -induced cardiotoxicity. Rats were randomly divided into four groups: Group 1, served as the control group, received normal saline. Group 2, served as the toxic group, received CFZ (4 mg/kg, intraperitoneally [i.p.]). Groups 3 and 4, served as treatment groups, and received CFZ with concomitant oral administration of AP in doses of 10 and 20 mg/kg/day, respectively. In the present study, administration of CFZ resulted in a significant increase in serum aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB), which were reversed by treatment with AP. CFZ resulted in a significant increase in heart malondialdehyde (MDA) contents and decrease in cardiac glutathione (GSH) level and catalase (CAT) enzyme activity which were significantly reversed by treatment with AP. Induction of cardiotoxicity by CFZ significantly increased caspase-3 enzyme activity which were reversed by treatment with AP. RT-PCR analysis revealed an increased mRNA expression of NF-κB, ERK and JNK which were reversed by treatment with AP in cardiac tissues. Western blot analysis revealed an increased expression of caspase-3 and NF-κB p65 and a decrease expression of inhibitory kappa B-alpha (Iκbα) with CFZ, which were reversed by treatment with AP. In conclusion, apremilast showed protective effect against CFZ-induced cardiotoxicity.
authors: a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
authors: Faisal
authors: F
authors: Imam
authors: a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
authors: Naif O
authors: NO
authors: Al-Harbi
authors: a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
authors: Mohammad Matar
authors: MM
authors: Al-Harbi
authors: a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
authors: Mushtaq Ahmad
authors: MA
authors: Ansari
authors: a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
authors: Mashal M
authors: MM
authors: Almutairi
authors: a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
authors: Musaad
authors: M
authors: Alshammari
authors: b Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Saudi Arabia.
authors: Talal Saad
authors: TS
authors: Almukhlafi
authors: b Department of Pharmacology, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-Kharj , Saudi Arabia.
authors: Mohd Nazam
authors: MN
authors: Ansari
authors: c King Khalid University Hospital, College of Medicine , King Saud University, Forensic Medicine and Toxicology Unit , Riyadh , Saudi Arabia.
authors: Khaldoon
authors: K
authors: Aljerian
authors: a Department of Pharmacology and Toxicology, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
authors: Sheikh Fayaz
authors: SF
authors: Ahmad
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D066126:Cardiotoxicity / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009842:Oligopeptides / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D009842:Oligopeptides; D013792:Thalidomide; C524865:carfilzomib; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C505730:apremilast
keywords: Cardiotoxicity; MAPK; apremilast; nuclear factor-kappa B; oxidative stress