کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8529322 | 1558857 | 2018 | 39 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy
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کلمات کلیدی
Pioglitazone (PubChem CID: 4829)Rosiglitazone (PubChem CID: 77999)Gefitinib (PubChem CID: 123631)Autophagy - اتوفاژیDrug repurposing - داروهای تجویزیphosphatase and tensin homolog - فسفاتاز و تنسین همولوگDrug resistance - مقاومت داروییEpidermal growth factor receptor tyrosine kinase inhibitor - مهار کننده تیروزین کیناز گیرنده فاکتور رشد اپیدرمالPeroxisome proliferator-activated receptor gamma - گاما گیرنده گیرنده فعال پرولیفیزوم فعال
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
We aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of non-small cell lung cancer (NSCLC). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates phosphatase and tensin homolog (PTEN) to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to resistance to EGFR TKIs. Therefore, PPARγ agonists are hypothesized to overcome EGFR TKI resistance. Using human NSCLC cell models with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARγ agonists was evaluated. PPARγ agonists were found to upregulate PTEN, subsequently inhibiting the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI). Chemical and genetic inhibition of PPARγ were shown to prevent this potentiation of anticancer activity by PPARγ agonists, thus confirming the crucial role played by PPARγ activation. Interestingly, the tested PPARγ agonists were also found to induce autophagy, as evidenced by the increased expression of an autophagy marker LC3-II and the autophagic degradation of p62/SQSTM1. PPARγ agonists-induced autophagic cell death was believed to contribute to the circumvention of resistance in PTEN-deficient cells because the genetic silencing of ATG5 (an autophagy mediator) was found to eliminate the drug potentiation effect by the PPARγ agonists. Our findings thus provide the basis for the rational and personalized use of PPARγ agonists in combination with EGFR TKIs in lung cancer patients.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 823, 15 March 2018, Pages 19-26
Journal: European Journal of Pharmacology - Volume 823, 15 March 2018, Pages 19-26
نویسندگان
Kenneth K.W. To, William K.K. Wu, Herbert H.F. Loong,