title: The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is a highly heterogeneous disease and internal tandem duplication mutation in FMS-like tyrosine-kinase-3 (FLT3-ITD) has a negative impact on outcome. Finding effective treatment regimens is desperately needed. In this study, we explored the inhibitory effect and mechanism of homoharringtonine (HHT) in combination with ibrutinib on FLT3-ITD mutant AML cells. Consequently, we observed a synergistic inhibitory effect when ibrutinib was combined with HHT to inhibit cell proliferation, induce apoptosis and arrest cell cycle at G0/G1 phase in MV4-11 and MOLM-13 leukemia cells. Our results indicate that the mechanisms of the combination effect are mainly via regulating the STAT5/Pim-2/C-Myc pathway, AKT pathway and Bcl-2 family, activating p21WAF1/CIP1 and inhibiting CCND/CDK complex protein. Interestingly, synergistic cytotoxicity of ibrutinib and HHT was dependent on both FLT3 and BTK. Here we provide a novel effective therapeutic approach for the treatment of AML patients with FLT3-ITD mutation.
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Chenying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Yile
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: ShuJuan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China.|Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006248:Harringtonines / Q000494:pharmacology*; D000077863:Homoharringtonine; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D010880:Piperidines; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D006248:Harringtonines; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000077863:Homoharringtonine; D051941:fms-Like Tyrosine Kinase 3; D000225:Adenine
keywords: FLT3-ITD; acute myeloid leukemia; homoharringtonine; ibrutinib