title: Molecular mechanisms of cardiotoxicity of gefitinib in vivo and in vitro rat cardiomyocyte: Role of apoptosis and oxidative stress.
abstract: Gefitinib (GEF) is a multi-targeted tyrosine kinase inhibitor with anti-cancer properties, yet few cases of cardiotoxicity has been reported as a significant side effect associated with GEF treatment. The main purpose of this study was to investigate the potential cardiotoxic effect of GEF and the possible mechanisms involved using in vivo and in vitro rat cardiomyocyte model. Treatment of rat cardiomyocyte H9c2 cell line with GEF (0, 1, 5, and 10μM) caused cardiomyocyte death and upregulation of hypertrophic gene markers, such as brain natriuretic peptides (BNP) and Beta-myosin heavy chain (β-MHC) in a concentration-dependent manner at the mRNA and protein levels associated with an increase in the percentage of hypertrophied cardiac cells. Mechanistically, GEF treatment caused proportional and concentration-dependent increases in the mRNA and protein expression levels of apoptotic markers caspase-3 and p53 which was accompanied with marked increases in the percentage of H9c2 cells underwent apoptosis/necrosis as compared to control. In addition, oxidative stress marker (heme oxygenase-1, HO-1) and the formation of reactive oxygen species were increased in response to GEF treatment. At the in vivo level, treatment of Wistar albino rats for 21days with GEF (20 and 30mg/kg) significantly increased the cardiac enzymes (CK, CKmb, and LDH) levels associated with histopathological changes indicative of cardiotoxicity. Similarly, in vivo GEF treatment increased the mRNA and protein levels of BNP and β-MHC whereas inhibited the antihypertrophoic gene (α-MHC) associated with increased the percentage of hypertrophied cells. Furthermore, the mRNA and protein expression levels of caspase-3, p53, and HO-1 genes and the percentage of apoptotic cells were significantly increased by GEF treatment, which was more pronounced at the 30mg/kg dose. In conclusion, GEF induces cardiotoxicity and cardiac hypertrophy in vivo and in vitro rat model through cardiac apoptotic cell death and oxidative stress pathways.
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: hkorashy@ksu.edu.sa.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Ibraheem M
authors.initials: IM
authors.lastname: Attafi
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mushtaq A
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Assiri
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Osamah M
authors.initials: OM
authors.lastname: Belali
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Sheik F
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Serology and Immunology department, PCLM, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Al-Alallah
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Fawaz E Al
authors.initials: FE
authors.lastname: Anazi
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Abdulqader A
authors.initials: AA
authors.lastname: Alhaider
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D006332:Cardiomegaly / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D066126:Cardiotoxicity; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011799:Quinazolines / Q000633:toxicity*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D000077156:Gefitinib
keywords: Apoptosis; BNP; Cardiac hypertrophy; Gefitinib; H9c2 cells; Oxidative stress; in vivo; β-MHC