Full metadata record
DC Field | Value | Language |
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dc.contributor.author | Gil, Hyo-Sun | - |
dc.contributor.author | Lee, Jeong-Hun | - |
dc.contributor.author | Farag, Ahmed K. | - |
dc.contributor.author | Hassan, Ahmed H. E. | - |
dc.contributor.author | Chung, Kyung-Sook | - |
dc.contributor.author | Choi, Jung-Hye | - |
dc.contributor.author | Roh, Eun-Joo | - |
dc.contributor.author | Lee, Kyung-Tae | - |
dc.date.accessioned | 2024-01-19T13:31:24Z | - |
dc.date.available | 2024-01-19T13:31:24Z | - |
dc.date.created | 2022-01-25 | - |
dc.date.issued | 2021-11 | - |
dc.identifier.issn | 2072-6694 | - |
dc.identifier.uri | https://pubs.kist.re.kr/handle/201004/116174 | - |
dc.description.abstract | Simple 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.language | English | - |
dc.publisher | MDPI | - |
dc.title | AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells | - |
dc.type | Article | - |
dc.identifier.doi | 10.3390/cancers13225849 | - |
dc.description.journalClass | 1 | - |
dc.identifier.bibliographicCitation | CANCERS, v.13, no.22 | - |
dc.citation.title | CANCERS | - |
dc.citation.volume | 13 | - |
dc.citation.number | 22 | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.identifier.wosid | 000723716800001 | - |
dc.identifier.scopusid | 2-s2.0-85119413015 | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.relation.journalResearchArea | Oncology | - |
dc.type.docType | Article | - |
dc.subject.keywordPlus | NF-KAPPA-B | - |
dc.subject.keywordPlus | DIARYL UREA | - |
dc.subject.keywordPlus | VITAMIN-E | - |
dc.subject.keywordPlus | DEATH | - |
dc.subject.keywordPlus | FAS | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | INDUCTION | - |
dc.subject.keywordPlus | PATHWAYS | - |
dc.subject.keywordPlus | MECHANISMS | - |
dc.subject.keywordPlus | DESIGN | - |
dc.subject.keywordAuthor | AKF-D52 | - |
dc.subject.keywordAuthor | non-small cell lung cancer (NSCLC) | - |
dc.subject.keywordAuthor | apoptosis | - |
dc.subject.keywordAuthor | autophagy | - |
dc.subject.keywordAuthor | reactive oxygen species (ROS) | - |
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