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المؤلفAlhoshani, Ali
المؤلفAlanazi, Fawaz E
المؤلفAlotaibi, Moureq R
المؤلفAttwa, Mohamed W
المؤلفKadi, Adnan A
المؤلفAldhfyan, Abdullah
المؤلفAkhtar, Sabah
المؤلفHourani, Shireen
المؤلفAgouni, Abdelali
المؤلفZeidan, Asad
المؤلفKorashy, Hesham M
تاريخ الإتاحة2020-06-16T20:19:43Z
تاريخ النشر2020-05-21
اسم المنشورChemical Research in Toxicology
المعرّفhttp://dx.doi.org/10.1021/acs.chemrestox.0c00005
الاقتباسAlhoshani A, Alanazi FE, Alotaibi MR, et al. 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 [published online ahead of print, 2020 May 21]. Chem Res Toxicol. 2020;10.1021/acs.chemrestox.0c00005. doi:10.1021/acs.chemrestox.0c00005
الرقم المعياري الدولي للكتاب0893-228X
معرّف المصادر الموحدhttp://hdl.handle.net/10576/15053
الملخصGefitinib (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, H9c2 cells and 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 and 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.
اللغةen
الناشرAmerican Chemical Society
الموضوعGefitinib
Caediotoxicity
H9c2 rat cardiomyocyte cells
CYP1A1
PTEN
FoxO3a
العنوانEGFR Inhibitor Gefitinib Induces Cardiotoxicity through the Modulation of Cardiac PTEN/Akt/FoxO3a Pathway and Reactive Metabolites Formation: and Rat Studies.
النوعArticle
ESSN1520-5010
dc.accessType Abstract Only


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