EGFR Inhibitor Gefitinib Induces Cardiotoxicity through the Modulation of Cardiac PTEN/Akt/FoxO3a Pathway and Reactive Metabolites Formation: and Rat Studies.
المؤلف | Alhoshani, Ali |
المؤلف | Alanazi, Fawaz E |
المؤلف | Alotaibi, Moureq R |
المؤلف | Attwa, Mohamed W |
المؤلف | Kadi, Adnan A |
المؤلف | Aldhfyan, Abdullah |
المؤلف | Akhtar, Sabah |
المؤلف | Hourani, Shireen |
المؤلف | Agouni, Abdelali |
المؤلف | Zeidan, Asad |
المؤلف | Korashy, Hesham M |
تاريخ الإتاحة | 2020-06-16T20:19:43Z |
تاريخ النشر | 2020-05-21 |
اسم المنشور | Chemical Research in Toxicology |
المعرّف | http://dx.doi.org/10.1021/acs.chemrestox.0c00005 |
الاقتباس | Alhoshani 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 للكتاب | 0893-228X |
الملخص | 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, 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. |
اللغة | en |
الناشر | American Chemical Society |
الموضوع | Gefitinib Caediotoxicity H9c2 rat cardiomyocyte cells CYP1A1 PTEN FoxO3a |
النوع | Article |
ESSN | 1520-5010 |
الملفات في هذه التسجيلة
الملفات | الحجم | الصيغة | العرض |
---|---|---|---|
لا توجد ملفات لها صلة بهذه التسجيلة. |
هذه التسجيلة تظهر في المجموعات التالية
-
أبحاث الطب [1418 items ]
-
أبحاث الصيدلة [1261 items ]