PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation

Abstract Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the poten...

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Autores principales:	Chao Hu, Mengxia Yu, Yanling Ren, Kongfei Li, Dominic M. Maggio, Chen Mei, Li Ye, Juying Wei, Jie Jin, Zhengping Zhuang, Hongyan Tong
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/989b895b4d6c446dbb40e8e4801513f0
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spelling	oai:doaj.org-article:989b895b4d6c446dbb40e8e4801513f02021-12-02T11:53:06ZPP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation10.1038/s41598-017-03058-42045-2322https://doaj.org/article/989b895b4d6c446dbb40e8e4801513f02017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03058-4https://doaj.org/toc/2045-2322Abstract Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the potential of LB100, a small-molecule protein phosphatase 2 A (PP2A) inhibitor, as a monotherapy and chemosensitizing agent for sAML using an in-vitro and in-vivo approach. We demonstrate that LB100 decreases cell viability through caspase activation and G2/M cell-cycle arrest. LB100 enhances daunorubicin (DNR) cytotoxicity resulting in decreased xenograft volumes and improved overall survival. LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3′ untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. Our research highlights the therapeutic potential of LB100, and provides new insights into the mechanism of LB100 chemosensitization.Chao HuMengxia YuYanling RenKongfei LiDominic M. MaggioChen MeiLi YeJuying WeiJie JinZhengping ZhuangHongyan TongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chao Hu Mengxia Yu Yanling Ren Kongfei Li Dominic M. Maggio Chen Mei Li Ye Juying Wei Jie Jin Zhengping Zhuang Hongyan Tong PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation
description	Abstract Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the potential of LB100, a small-molecule protein phosphatase 2 A (PP2A) inhibitor, as a monotherapy and chemosensitizing agent for sAML using an in-vitro and in-vivo approach. We demonstrate that LB100 decreases cell viability through caspase activation and G2/M cell-cycle arrest. LB100 enhances daunorubicin (DNR) cytotoxicity resulting in decreased xenograft volumes and improved overall survival. LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3′ untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. Our research highlights the therapeutic potential of LB100, and provides new insights into the mechanism of LB100 chemosensitization.
format	article
author	Chao Hu Mengxia Yu Yanling Ren Kongfei Li Dominic M. Maggio Chen Mei Li Ye Juying Wei Jie Jin Zhengping Zhuang Hongyan Tong
author_facet	Chao Hu Mengxia Yu Yanling Ren Kongfei Li Dominic M. Maggio Chen Mei Li Ye Juying Wei Jie Jin Zhengping Zhuang Hongyan Tong
author_sort	Chao Hu
title	PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation
title_short	PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation
title_full	PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation
title_fullStr	PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation
title_full_unstemmed	PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation
title_sort	pp2a inhibition from lb100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via mir-181b-1 upregulation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/989b895b4d6c446dbb40e8e4801513f0
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PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation

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