title: Rutin Attenuates Carfilzomib-Induced Cardiotoxicity Through Inhibition of NF-κB, Hypertrophic Gene Expression and Oxidative Stress.
abstract: Carfilzomib is a proteasome inhibitor, commonly used in multiple myeloma, but its clinical use may be limited due to cardiotoxicity. This study was aimed to evaluate the influence of rutin in carfilzomib-induced cardiotoxicity in rats. Wistar albino male rats weighing 200-250 g (approximately 10 weeks old) were taken for this study. Animals were divided into four groups of six animals each. Group 1 served as normal control (NC), received normal saline; group 2 animals received carfilzomib (dissolved in 1 % DMSO) alone; group 3 animals received rutin (20 mg/kg) + carfilzomib; and group 4 animals received rutin (40 mg/kg) + carfilzomib. Hematological changes, biochemical changes, oxidative stress, hypertrophic gene expression, apoptotic gene expression, NFκB and IκB-α protein expression and histopathological evaluation were done to confirm the finding of carfilzomib-induced cardiotoxicity. Treatment with rutin decreased the carfilzomib-induced changes in cardiac enzymes such as lactate dehydrogenase, creatine kinase (CK) and CK-MB. For the assessment of cardiotoxicity, we further evaluated cardiac hypertrophic gene and apoptotic gene expression such as α-MHC, β-MHC and BNP and NF-κB and p53 gene expression, respectively, using RT-PCR. Western blot analysis showed that rutin treatment prevented the activation of NF-κB by increasing the expression of IκB-α. Rutin also attenuated the effects of carfilzomib on oxidant-antioxidant including malondialdehyde and reduced glutathione. Histopathological study clearly confirmed that rutin attenuated carfilzomib-induced cardiotoxicity in rats.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia. fimam@ksu.edu.sa.
authors.forename: Faisal
authors.initials: F
authors.lastname: Imam
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Naif O
authors.initials: NO
authors.lastname: Al-Harbi
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Al-Harbia
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Mushtaq Ahmad
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Sayed-Ahmed
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia.
authors.forename: Mahmoud N
authors.initials: MN
authors.lastname: Nagi
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia.
authors.forename: Md
authors.initials: M
authors.lastname: Khalid Anwer
authors.affiliation: Glocal School of Pharmacy, Glocal University, Saharanpur, India.
authors.forename: Imran
authors.initials: I
authors.lastname: Kazmi
authors.affiliation: Glocal School of Pharmacy, Glocal University, Saharanpur, India.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Afzal
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Madinah, Kingdom of Saudi Arabia.
authors.forename: Saleh
authors.initials: S
authors.lastname: Bahashwan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D066126:Cardiotoxicity; D019610:Cytoprotection; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D012431:Rutin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D009842:Oligopeptides; D012333:RNA, Messenger; D012431:Rutin; C524865:carfilzomib
keywords: Apoptosis; Cardiotoxicity; Carfilzomib; Natriuretic peptide; Nuclear factor-kappa B; Oxidative stress; Rutin