The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia

Li, Xia; Yin, Xiufeng; Wang, Huafeng; Huang, Jiansong; Yu, Mengxia; Ma, Zeyu; Li, Chenying; Zhou, Yile; Yan, Xiao; Huang, Shujuan; Jin, Jie

doi:10.18632/oncotarget.14463

Cited by 18 publications

(7 citation statements)

References 33 publications

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“…Since this drug does not target specific proteins, its success is mainly due to the fact that it can disturb proteins with rapid turnover such as the leukemic cells’ upregulated short-lived oncoproteins BCR-ABL1 and antiapoptotic proteins (Mcl-1, Myc) leading to cells apoptosis [ 71 ]. Recently, other mechanisms indicated that it could also affect signaling pathways, like the Jak-stat5 pathway, by regulating protein tyrosine kinase phosphorylation [ 72 ] and by activating the TGF-β pathway through phosphorylation of smad3 [ 73 ].…”

Section: Secondary Metabolites From Plants As Anticancer Agentsmentioning

confidence: 99%

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

Seca

Pinto

2018

IJMS

539

303

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Cancer is a multistage process resulting in an uncontrolled and abrupt division of cells and is one of the leading causes of mortality. The cases reported and the predictions for the near future are unthinkable. Food and Drug Administration data showed that 40% of the approved molecules are natural compounds or inspired by them, from which, 74% are used in anticancer therapy. In fact, natural products are viewed as more biologically friendly, that is less toxic to normal cells. In this review, the most recent and successful cases of secondary metabolites, including alkaloid, diterpene, triterpene and polyphenolic type compounds, with great anticancer potential are discussed. Focusing on the ones that are in clinical trial development or already used in anticancer therapy, therefore successful cases such as paclitaxel and homoharringtonine (in clinical use), curcumin and ingenol mebutate (in clinical trials) will be addressed. Each compound’s natural source, the most important steps in their discovery, their therapeutic targets, as well as the main structural modifications that can improve anticancer properties will be discussed in order to show the role of plants as a source of effective and safe anticancer drugs.

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Section: Secondary Metabolites From Plants As Anticancer Agentsmentioning

confidence: 99%

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

Seca

Pinto

2018

IJMS

539

303

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“…P53 and p21 are important tumor suppressor proteins, and p53 induces the expression of p21 [10]. HHT has been shown to enhance p53/p21 expression in FLT3-ITD mutant AML [11], but this effect in LSCs and the consequence for cell proliferation are not well understood. Moreover, p53/p21 expression is induced by Notch ligand in myeloid lineage cells overexpressing Notch/Hes1 [12].…”

Section: Introductionmentioning

confidence: 99%

Synergistic killing effects of homoharringtonine and arsenic trioxide on acute myeloid leukemia stem cells and the underlying mechanisms

Tan

Zhang

Yuan

et al. 2019

J Exp Clin Cancer Res

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Background At present, it is generally believed that leukemia stem cells are the source of AML, so the killing of leukemia stem cells has become important. Previous studies have suggested that HHT combined with ATO can synergistically kill U937 cells, and HHT has also demonstrated the ability to kill leukemia stem cells. We evaluated whether HHT combined with ATO can systematically kill leukemia stem cells (LSCs) and explored the synergistic effect and molecular mechanism. Methods CCK-8 was used to detect cell viability. The changes of cell cycle (PI staining), apoptosis (Annexin V/PI) and surface markers (CD34, CD38, CD96, CD45) were detected by flow cytometry. The cells of CD34+ primary leukemia and CD38- KG-1, and TF-1 were separated by flow cytometry. High-throughput mRNA sequencing was used to analysis mRNA level changes after the application of the two drugs. Western blot was used to verify the changes of pathway protein expression. NRG mice were used as the receptor of xenograft model. Histological H&E staining assess the invaded ability of leukemia cells, and laser scanning confocal microscopy evaluated the molecule markers change. Results HHT and ATO synergistically killed KG-1 (CD34 + /CD96 + /CD38 + / − ) and Kasumi-1 (CD34 + /CD38 − ) cells. Their combination had a stronger effect of inducing apoptosis and blocking the cell cycle than HHT or ATO administrator alone, meanwhile significantly reducing the numbers of LSCs. Further, CD34 + CD38 − cells in KG-1, KG-1a, TF-1, and primary leukemia cells were more sensitive to HHT and ATO. High-throughput mRNA sequencing suggested that HHT alone could significantly upregulate molecules related to the Notch, P53, and NF-κB signaling pathways. When combined with ATO, HHT further upregulated P53, whereas HHT-induced NF-κB pathway activation was significantly suppressed. Western blot analysis verified the change of protein expression in the above pathways and further demonstrated that GSI, could eliminate these effects. In vivo, HHT combined with ATO significantly reduced the LSC burden, and weakened the expression of LSC markers. Conclusions This is the first evidence that HHT combined with arsenic can synergistically kill LSCs in vitro and in vivo, along with identification of the underlying mechanism, highlighting a potentially effective treatment strategy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1295-8) contains supplementary material, which is available to authorized users.

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“…Although FLT3 tyrosine kinase inhibitors (TKI) have been developed to treat FLT3 -mutant AML patients, limited efficacy was observed because of relapse and rapid drug resistance [27]. Recently, we and others observed that HHT behaved a sensitive cytotoxic effect on FLT3 -ITD (+) AML cells [28], [29]. As many works highlighted, Hsp90 is a molecular chaperone of mutant FLT3 which is involved in holding conformation, stabilization and function of oncoproteins.…”

Section: Discussionmentioning

confidence: 99%

Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia

Zhuang

et al. 2019

Translational Oncology

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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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The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukemia

Cited by 18 publications

References 33 publications

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

Synergistic killing effects of homoharringtonine and arsenic trioxide on acute myeloid leukemia stem cells and the underlying mechanisms

Homoharringtonine Combined with the Heat Shock Protein 90 Inhibitor IPI504 in the Treatment of FLT3-ITD Acute Myeloid Leukemia

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