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dc.contributor.authorGil, Hyo-Sun-
dc.contributor.authorLee, Jeong-Hun-
dc.contributor.authorFarag, Ahmed K.-
dc.contributor.authorHassan, Ahmed H. E.-
dc.contributor.authorChung, Kyung-Sook-
dc.contributor.authorChoi, Jung-Hye-
dc.contributor.authorRoh, Eun-Joo-
dc.contributor.authorLee, Kyung-Tae-
dc.date.accessioned2024-01-19T13:31:24Z-
dc.date.available2024-01-19T13:31:24Z-
dc.date.created2022-01-25-
dc.date.issued2021-11-
dc.identifier.issn2072-6694-
dc.identifier.urihttps://pubs.kist.re.kr/handle/201004/116174-
dc.description.abstractSimple Summary:& nbsp;We previously reported the antiproliferative effects of a phenoxypyridine urea derivative. In this study, we aimed to investigate the antiproliferative effects of 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52) in non-small cell lung cancer cells. We found that (i) AKF-D52 induces apoptosis in caspase-dependent and caspase-independent pathways; (ii) AKF-D52-induced apoptosis is caused by the clustering of a death-inducing signaling complex and mitochondrial-dependent signaling; (iii) AKF-D52 induces cytoprotective autophagy, and pre-treatment with an autophagy inhibitor enhances the apoptotic effect of AKF-D52; and (iv) AKF-D52-induced apoptosis and autophagy are attenuated by the reactive oxygen species (ROS) scavenger a-tocopherol. Furthermore, AKF-D52 suppressed tumor growth in a xenograft mouse model. Collectively, our findings regarding the efficacy and molecular mechanisms of AKF-D52 identify this compound as a potential therapeutic agent for the treatment of lung cancer.<br>Previously, we discovered that 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a synthetic phenoxypyrimidine urea derivative, acts as a growth inhibitor of various cancer cell types. In this study, we elucidated the antiproliferative properties of AFK-D52 and underlying mechanisms in non-small cell lung cancer (NSCLC) cells and an A549 xenograft animal model. AKF-D52 was found to induce both caspase-dependent and -independent apoptotic cell death. Furthermore, the mitochondrial component of the AKF-D52-induced apoptosis mechanism involves a reduction in mitochondrial membrane potential and regulation in B cell lymphoma-2 family protein expression. Moreover, AKF-D52 activates the extrinsic pathway through up-regulated expression of death receptor 3 and Fas and then the formation of a death-inducing signaling complex. AKF-D52 also induced autophagy by increasing acidic vesicular organelle formation and microtubule-associated protein 1A/1B-light chain 3-II levels and reducing p62 levels. Notably, pretreatment with autophagy inhibitors enhanced AKF-D52-induced cell death, indicating that the induced autophagy is cytoprotective. AKF-D52 treatment also triggered reactive oxygen species (ROS) production in NSCLC cells, whereas the antioxidant a-tocopherol abolished AKF-D52-induced cell death. In a xenograft lung cancer mouse model, AKF-D52 administration attenuated tumor growth by inducing apoptosis and autophagy in tumor tissues. Collectively, our data indicate that AKF-D52-induced ROS production plays a role in mediating apoptosis and cytoprotective autophagy in NSCLC.-
dc.languageEnglish-
dc.publisherMDPI-
dc.titleAKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells-
dc.typeArticle-
dc.identifier.doi10.3390/cancers13225849-
dc.description.journalClass1-
dc.identifier.bibliographicCitationCANCERS, v.13, no.22-
dc.citation.titleCANCERS-
dc.citation.volume13-
dc.citation.number22-
dc.description.isOpenAccessN-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
dc.identifier.wosid000723716800001-
dc.identifier.scopusid2-s2.0-85119413015-
dc.relation.journalWebOfScienceCategoryOncology-
dc.relation.journalResearchAreaOncology-
dc.type.docTypeArticle-
dc.subject.keywordPlusNF-KAPPA-B-
dc.subject.keywordPlusDIARYL UREA-
dc.subject.keywordPlusVITAMIN-E-
dc.subject.keywordPlusDEATH-
dc.subject.keywordPlusFAS-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusINDUCTION-
dc.subject.keywordPlusPATHWAYS-
dc.subject.keywordPlusMECHANISMS-
dc.subject.keywordPlusDESIGN-
dc.subject.keywordAuthorAKF-D52-
dc.subject.keywordAuthornon-small cell lung cancer (NSCLC)-
dc.subject.keywordAuthorapoptosis-
dc.subject.keywordAuthorautophagy-
dc.subject.keywordAuthorreactive oxygen species (ROS)-
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