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EGFR Inhibitor Gefitinib Induces Cardiotoxicity through the Modulation of Cardiac PTEN/Akt/FoxO3a Pathway and Reactive Metabolites Formation: In Vivo and in Vitro Rat Studies.
Alhoshani, Ali; Alanazi, Fawaz E; Alotaibi, Moureq R; Attwa, Mohamed W; Kadi, Adnan A; Aldhfyan, Abdullah; Akhtar, Sabah; Hourani, Shireen; Agouni, Abdelali; Zeidan, Asad; Korashy, Hesham M.
Affiliation
  • Alhoshani A; Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • Alanazi FE; Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • Alotaibi MR; Security Forces Hospital Program, P.O. Box 3643, Riyadh 11481, Saudi Arabia.
  • Attwa MW; Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • Kadi AA; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • Aldhfyan A; Students' University Hospital, Mansoura University, Mansoura 35516, Egypt.
  • Akhtar S; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • Hourani S; Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • Agouni A; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
  • Zeidan A; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
  • Korashy HM; Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
Chem Res Toxicol ; 33(7): 1719-1728, 2020 07 20.
Article in En | MEDLINE | ID: mdl-32370496
Gefitinib (GEF) is a selective inhibitor of the epidermal growth factor receptor (EGFR) used to treat non-small cell lung cancer. Yet, few cases of cardiotoxicity have been reported. However, the role of the PTEN/Akt/FoxO3a pathway, which mediates GEF anticancer activity, in GEF cardiotoxicity remains unclear. For this purpose, in vitro H9c2 cells and in vivo rat cardiomyocytes were utilized as study models. Treatment of H9c2 cells and Sprague-Dawley rats with GEF significantly induced the expression of hypertrophic and apoptotic markers at mRNA and protein levels with an increased plasma level of troponin. This was accompanied by induction of autophagy and mitochondrial dysfunction in H9c2 cells. Inhibition of cardiac EGFR activity and Akt cellular content of in vitro and in vivo rat cardiomyocytes by GEF increased PTEN and FoxO3a gene expression and cellular content. Importantly, treatment of H9c2 cells with PI3K/Akt inhibitor increased PTEN and FoxO3a mRNA expression associated with potentiation of GEF cardiotoxicity. In addition, by using LC-MS/MS, we showed that GEF is metabolized in the rat heart microsomes into one cyanide- and two methoxylamine-adduct reactive metabolites, where their formation was entirely blocked by CYP1A1 inhibitor, α-naphthoflavone. The current study concludes that GEF induces cardiotoxicity through modulating the expression and function of the cardiac PTEN/AKT/FoxO3a pathway and the formation of CYP1A1-mediated reactive metabolites.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Kinase Inhibitors / PTEN Phosphohydrolase / Proto-Oncogene Proteins c-akt / Cardiotoxicity / ErbB Receptors / Forkhead Box Protein O3 / Gefitinib / Antineoplastic Agents Type of study: Prognostic_studies Limits: Animals Language: En Journal: Chem Res Toxicol Journal subject: TOXICOLOGIA Year: 2020 Document type: Article Affiliation country: Saudi Arabia Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Kinase Inhibitors / PTEN Phosphohydrolase / Proto-Oncogene Proteins c-akt / Cardiotoxicity / ErbB Receptors / Forkhead Box Protein O3 / Gefitinib / Antineoplastic Agents Type of study: Prognostic_studies Limits: Animals Language: En Journal: Chem Res Toxicol Journal subject: TOXICOLOGIA Year: 2020 Document type: Article Affiliation country: Saudi Arabia Country of publication: United States