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Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia
As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449739/ https://www.ncbi.nlm.nih.gov/pubmed/30953928 http://dx.doi.org/10.1016/j.tranon.2019.02.016 |
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author | Wu, Zhaoxing Zhuang, Haifeng Yu, Qingfeng Zhang, Xuzhao Jiang, Xudong Lu, Xiaoya Xu, Ying Yang, Linlin Wu, Bowen Ma, An Zhang, Lei Xiao, Xibin Liang, Yun Gao, Ruilan Shen, Jianping Xu, Rongzhen |
author_facet | Wu, Zhaoxing Zhuang, Haifeng Yu, Qingfeng Zhang, Xuzhao Jiang, Xudong Lu, Xiaoya Xu, Ying Yang, Linlin Wu, Bowen Ma, An Zhang, Lei Xiao, Xibin Liang, Yun Gao, Ruilan Shen, Jianping Xu, Rongzhen |
author_sort | Wu, Zhaoxing |
collection | PubMed |
description | As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML. |
format | Online Article Text |
id | pubmed-6449739 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-64497392019-04-15 Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia Wu, Zhaoxing Zhuang, Haifeng Yu, Qingfeng Zhang, Xuzhao Jiang, Xudong Lu, Xiaoya Xu, Ying Yang, Linlin Wu, Bowen Ma, An Zhang, Lei Xiao, Xibin Liang, Yun Gao, Ruilan Shen, Jianping Xu, Rongzhen Transl Oncol Original article As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML. Neoplasia Press 2019-04-04 /pmc/articles/PMC6449739/ /pubmed/30953928 http://dx.doi.org/10.1016/j.tranon.2019.02.016 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Wu, Zhaoxing Zhuang, Haifeng Yu, Qingfeng Zhang, Xuzhao Jiang, Xudong Lu, Xiaoya Xu, Ying Yang, Linlin Wu, Bowen Ma, An Zhang, Lei Xiao, Xibin Liang, Yun Gao, Ruilan Shen, Jianping Xu, Rongzhen Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia |
title | Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia |
title_full | Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia |
title_fullStr | Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia |
title_full_unstemmed | Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia |
title_short | Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia |
title_sort | homoharringtonine combined with the heat shock protein 90 inhibitor ipi504 in the treatment of flt3-itd acute myeloid leukemia |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449739/ https://www.ncbi.nlm.nih.gov/pubmed/30953928 http://dx.doi.org/10.1016/j.tranon.2019.02.016 |
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