{'fraction_non_alphanumeric': 0.02575107296137339, 'fraction_numerical': 0.011036174126302882, 'mean_word_length': 5.4, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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.

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 PTEN/Akt/FoxO3a pathway, which is mediating GEF anticancer activity, in GEF cardiotoxicity remains unclear. For this purpose, in vitro H9c2 cell and in vivo rat cardiomyocyte 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 increased plasma level of troponin. This was accompanied with induction of autophagy and mitochondrial dysfunction in H9c2 cells. Inhibition of cardiac EGFR activity and Akt cellular content in vitro and in vivo rat cardiomyocyte by GEF increased PTEN and FoxO3a genes expression and cellular content. In addition, by using LC-MS/MS, GEF is metabolized in the rat heart microsomes into one cyanide- and two methoxylamine-adducts reactive metabolites, where their formation was entirely blocked by CYP1A1 inhibitor, -naphthoflavone. Importantly, treatment of H9c2 cells with PI3K/Akt inhibitor increased PTEN and FoxO3a mRNA expression associated with potentiation of GEF cardiotoxicity. The current study concluded that GEF induces cardiotoxicity through modulating the expression/function of cardiac PTEN/AKT/FoxO3a pathway and formation of CYP1A1-mediated reactive metabolites.