RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma

<b>Background:</b> Malignant glioma (MG) is an aggressive malignant brain tumor. Despite advances in multidisciplinary treatment, overall survival rates remain low. A trifluoroethyl amide derivative of 2-cyano-3-,12-dioxoolean-1,9-dien-28-oic acid (CDDO), CDDO–trifluoroethyl amide (CDDO–...

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Autores principales:	Tai-Hsin Tsai, Ann-Shung Lieu, Tzuu-Yuan Huang, Aij-Lie Kwan, Chih-Lung Lin, Yi-Chiang Hsu
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	RTA404 malignant glioma apoptosis checkpoint kinase Medicine R
Acceso en línea:	https://doaj.org/article/511de4c9be2447bebdd9b447628e9820
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spelling	oai:doaj.org-article:511de4c9be2447bebdd9b447628e98202021-11-11T17:29:01ZRTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma10.3390/jcm102148052077-0383https://doaj.org/article/511de4c9be2447bebdd9b447628e98202021-10-01T00:00:00Zhttps://www.mdpi.com/2077-0383/10/21/4805https://doaj.org/toc/2077-0383<b>Background:</b> Malignant glioma (MG) is an aggressive malignant brain tumor. Despite advances in multidisciplinary treatment, overall survival rates remain low. A trifluoroethyl amide derivative of 2-cyano-3-,12-dioxoolean-1,9-dien-28-oic acid (CDDO), CDDO–trifluoroethyl amide (CDDO–TFEA) is a nuclear erythroid 2-related factor 2/antioxidant response element pathway activator. RTA404 is used to inhibit proliferation and induce apoptosis in cancer cells. However, its effect on tumorigenesis in glioma is unclear. <b>Methods:</b> This in vitro study evaluated the effects of RTA404 on MG cells. We treated U87MG cell lines with RTA404 and performed assessments of apoptosis and cell cycle distributions. DNA content and apoptosis induction were subjected to flow cytometry analysis. The mitotic index was assessed based on MPM-2 expression. Protein expression was analyzed through Western blotting. <b>Results:</b> RTA404 significantly inhibited the cell viability and induced cell apoptosis on the U87MG cell line. The Annexin-FITC/PI assay revealed significant changes in the percentage of apoptotic cells. Treatment with RTA404 led to a significant reduction in the U87MG cells’ mitochondrial membrane potential. A significant rise in the percentage of caspase-3 activity was detected in the treated cells. In addition, these results suggest that cells pass the G2 checkpoint without cell cycle arrest by RTA404 treatment in the MPM-2 staining. An analysis of CHK1, CHK2, and p-CHK2 expression suggested that the DNA damage checkpoint system seems also to be activated by RTA404 treatment in established U87MG cells. Therefore, RTA404 may not only activate the DNA damage checkpoint system, it may also exert apoptosis in established U87MG cells. <b>Conclusions:</b> RTA404 inhibits the cell viability of gliomas and induces cancer cell apoptosis through intrinsic apoptotic pathway in Malignant glioma. In addition, the DNA damage checkpoint system seems also to be activated by RTA404. Taken together, RTA404 activated the DNA damage checkpoint system and induced apoptosis through intrinsic apoptotic pathways in established U87MG cells.Tai-Hsin TsaiAnn-Shung LieuTzuu-Yuan HuangAij-Lie KwanChih-Lung LinYi-Chiang HsuMDPI AGarticleRTA404malignant gliomaapoptosischeckpoint kinaseMedicineRENJournal of Clinical Medicine, Vol 10, Iss 4805, p 4805 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	RTA404 malignant glioma apoptosis checkpoint kinase Medicine R
spellingShingle	RTA404 malignant glioma apoptosis checkpoint kinase Medicine R Tai-Hsin Tsai Ann-Shung Lieu Tzuu-Yuan Huang Aij-Lie Kwan Chih-Lung Lin Yi-Chiang Hsu RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma
description	<b>Background:</b> Malignant glioma (MG) is an aggressive malignant brain tumor. Despite advances in multidisciplinary treatment, overall survival rates remain low. A trifluoroethyl amide derivative of 2-cyano-3-,12-dioxoolean-1,9-dien-28-oic acid (CDDO), CDDO–trifluoroethyl amide (CDDO–TFEA) is a nuclear erythroid 2-related factor 2/antioxidant response element pathway activator. RTA404 is used to inhibit proliferation and induce apoptosis in cancer cells. However, its effect on tumorigenesis in glioma is unclear. <b>Methods:</b> This in vitro study evaluated the effects of RTA404 on MG cells. We treated U87MG cell lines with RTA404 and performed assessments of apoptosis and cell cycle distributions. DNA content and apoptosis induction were subjected to flow cytometry analysis. The mitotic index was assessed based on MPM-2 expression. Protein expression was analyzed through Western blotting. <b>Results:</b> RTA404 significantly inhibited the cell viability and induced cell apoptosis on the U87MG cell line. The Annexin-FITC/PI assay revealed significant changes in the percentage of apoptotic cells. Treatment with RTA404 led to a significant reduction in the U87MG cells’ mitochondrial membrane potential. A significant rise in the percentage of caspase-3 activity was detected in the treated cells. In addition, these results suggest that cells pass the G2 checkpoint without cell cycle arrest by RTA404 treatment in the MPM-2 staining. An analysis of CHK1, CHK2, and p-CHK2 expression suggested that the DNA damage checkpoint system seems also to be activated by RTA404 treatment in established U87MG cells. Therefore, RTA404 may not only activate the DNA damage checkpoint system, it may also exert apoptosis in established U87MG cells. <b>Conclusions:</b> RTA404 inhibits the cell viability of gliomas and induces cancer cell apoptosis through intrinsic apoptotic pathway in Malignant glioma. In addition, the DNA damage checkpoint system seems also to be activated by RTA404. Taken together, RTA404 activated the DNA damage checkpoint system and induced apoptosis through intrinsic apoptotic pathways in established U87MG cells.
format	article
author	Tai-Hsin Tsai Ann-Shung Lieu Tzuu-Yuan Huang Aij-Lie Kwan Chih-Lung Lin Yi-Chiang Hsu
author_facet	Tai-Hsin Tsai Ann-Shung Lieu Tzuu-Yuan Huang Aij-Lie Kwan Chih-Lung Lin Yi-Chiang Hsu
author_sort	Tai-Hsin Tsai
title	RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma
title_short	RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma
title_full	RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma
title_fullStr	RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma
title_full_unstemmed	RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma
title_sort	rta404, an activator of nrf2, activates the checkpoint kinases and induces apoptosis through intrinsic apoptotic pathway in malignant glioma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/511de4c9be2447bebdd9b447628e9820
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RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma

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