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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2019
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.
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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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