Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts

Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the...

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Autores principales:	Masashi Okada, Shuhei Suzuki, Keita Togashi, Asuka Sugai, Masahiro Yamamoto, Chifumi Kitanaka
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	glioma stem cell anti-folate RFC-1 brain tumor initiating cells JNK serial transplantation assay Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/e5acf3466c7b4aacadf36112ce933231
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spelling	oai:doaj.org-article:e5acf3466c7b4aacadf36112ce9332312021-11-11T17:06:33ZTargeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts10.3390/ijms2221116331422-00671661-6596https://doaj.org/article/e5acf3466c7b4aacadf36112ce9332312021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11633https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.Masashi OkadaShuhei SuzukiKeita TogashiAsuka SugaiMasahiro YamamotoChifumi KitanakaMDPI AGarticleglioma stem cellanti-folateRFC-1brain tumor initiating cellsJNKserial transplantation assayBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11633, p 11633 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glioma stem cell anti-folate RFC-1 brain tumor initiating cells JNK serial transplantation assay Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	glioma stem cell anti-folate RFC-1 brain tumor initiating cells JNK serial transplantation assay Biology (General) QH301-705.5 Chemistry QD1-999 Masashi Okada Shuhei Suzuki Keita Togashi Asuka Sugai Masahiro Yamamoto Chifumi Kitanaka Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts
description	Glioblastoma (GBM) is one of the deadliest of all human cancers. Developing therapies targeting GBM cancer stem cells or glioma stem cells (GSCs), which are deemed responsible for the malignancy of GBM due to their therapy resistance and tumor-initiating capacity, is considered key to improving the dismal prognosis of GBM patients. In this study, we found that folate antagonists, such as methotrexate (MTX) and pemetrexed, are selectively cytotoxic to GSCs, but not to their differentiated counterparts, normal fibroblasts, or neural stem cells in vitro, and that the high sensitivity of GCSs to anti-folates may be due to the increased expression of RFC-1/SLC19A1, the reduced folate carrier that transports MTX into cells, in GSCs. Of note, in an in vivo serial transplantation model, MTX alone failed to exhibit anti-GSC effects but promoted the anti-GSC effects of CEP1347, an inducer of GSC differentiation. This suggests that folate metabolism, which plays an essential role specifically in GSCs, is a promising target of anti-GSC therapy, and that the combination of cytotoxic and differentiation therapies may be a novel and promising approach to effectively eliminate cancer stem cells.
format	article
author	Masashi Okada Shuhei Suzuki Keita Togashi Asuka Sugai Masahiro Yamamoto Chifumi Kitanaka
author_facet	Masashi Okada Shuhei Suzuki Keita Togashi Asuka Sugai Masahiro Yamamoto Chifumi Kitanaka
author_sort	Masashi Okada
title	Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts
title_short	Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts
title_full	Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts
title_fullStr	Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts
title_full_unstemmed	Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts
title_sort	targeting folate metabolism is selectively cytotoxic to glioma stem cells and effectively cooperates with differentiation therapy to eliminate tumor-initiating cells in glioma xenografts
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e5acf3466c7b4aacadf36112ce933231
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Targeting Folate Metabolism Is Selectively Cytotoxic to Glioma Stem Cells and Effectively Cooperates with Differentiation Therapy to Eliminate Tumor-Initiating Cells in Glioma Xenografts

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