AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells

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 proper...

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Autores principales:	Hyo-Sun Gil, Jeong-Hun Lee, Ahmed K. Farag, Ahmed H. E. Hassan, Kyung-Sook Chung, Jung-Hye Choi, Eun-Joo Roh, Kyung-Tae Lee
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	AKF-D52 non-small cell lung cancer (NSCLC) apoptosis autophagy reactive oxygen species (ROS) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f52f7ce6b4b14e9ca8f82f05b51cd34c
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spelling	oai:doaj.org-article:f52f7ce6b4b14e9ca8f82f05b51cd34c2021-11-25T17:04:43ZAKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells10.3390/cancers132258492072-6694https://doaj.org/article/f52f7ce6b4b14e9ca8f82f05b51cd34c2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5849https://doaj.org/toc/2072-6694Previously, 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 α-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.Hyo-Sun GilJeong-Hun LeeAhmed K. FaragAhmed H. E. HassanKyung-Sook ChungJung-Hye ChoiEun-Joo RohKyung-Tae LeeMDPI AGarticleAKF-D52non-small cell lung cancer (NSCLC)apoptosisautophagyreactive oxygen species (ROS)Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5849, p 5849 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	AKF-D52 non-small cell lung cancer (NSCLC) apoptosis autophagy reactive oxygen species (ROS) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	AKF-D52 non-small cell lung cancer (NSCLC) apoptosis autophagy reactive oxygen species (ROS) Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hyo-Sun Gil Jeong-Hun Lee Ahmed K. Farag Ahmed H. E. Hassan Kyung-Sook Chung Jung-Hye Choi Eun-Joo Roh Kyung-Tae Lee AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells
description	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 α-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.
format	article
author	Hyo-Sun Gil Jeong-Hun Lee Ahmed K. Farag Ahmed H. E. Hassan Kyung-Sook Chung Jung-Hye Choi Eun-Joo Roh Kyung-Tae Lee
author_facet	Hyo-Sun Gil Jeong-Hun Lee Ahmed K. Farag Ahmed H. E. Hassan Kyung-Sook Chung Jung-Hye Choi Eun-Joo Roh Kyung-Tae Lee
author_sort	Hyo-Sun Gil
title	AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells
title_short	AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells
title_full	AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells
title_fullStr	AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells
title_full_unstemmed	AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells
title_sort	akf-d52, a synthetic phenoxypyrimidine-urea derivative, triggers extrinsic/intrinsic apoptosis and cytoprotective autophagy in human non-small cell lung cancer cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f52f7ce6b4b14e9ca8f82f05b51cd34c
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AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells

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