Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells

Ji, Qing; Ding, Ye; Sun, Yue; Zhang, Yu; Gao, Huier; Song, Haiqu; Yang, Moon-Sik; Liu, Xiaolei; Zhang, Zi-xiang; Li, Yinghui; Gao, Yingdai

doi:10.18632/oncotarget.11342

Cited by 46 publications

(37 citation statements)

References 33 publications

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“…DMAMCL is a novel agent that has an effect of anti-tumor growth and anti-inflammation. DMAMCL reduces tumor proliferation in glioma cells in vitro and in vivo [23], and selectively deracinates AML stem and progenitor cells in vitro and in vivo [36]. DMAMCL significantly suppresses the growth of leukemia cells in vitro and tumorigenesis in a zebrafish xenograft model in vivo [35].…”

Section: Discussionmentioning

confidence: 99%

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

Hua

et al. 2019

J Exp Clin Cancer Res

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Background Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children with poor survival. New treatment approaches are urgently needed to improve treatment efficacy in RMS patients. DMAMCL is a novel agent from Asteraceae family that has been tested in phase I clinical trials in adult glioma in Australia. Methods Five RMS cell lines (RD, RH18, RH28, RH30 and RH41) were used. The in vitro anti-tumor effect of DMAMCL, alone or in combination with VCR or Epirubicin, was studied using MTS assay or IncuCyte-Zoom cell confluency assay, and further validated by xenograft-mouse model in vivo. Changes in caspase-3/7 activity, cell-cycle progression and generation of ROS after DMAMCL treatment were investigated. Bim mRNA expression was measured by RT-qPCR, and protein expressions of Bim and phosphorylated-NF-κB(p65) by Western blotting. Small interfering RNAs (siRNA) of Bim were used to study the role of Bim in DMAMCL-induced cell death. Results In vitro, DMAMCL treatment induced a dose-dependent increase in cell death that could be blocked by pan-caspase-inhibitor-Z-VAD-fmk in five RMS cell lines. The percent of cells in SubG1 phase and activities of caspase-3/7 increased after DMAMCL treatment; The combination of DMAMCL with VCR or Epirubicin significantly increased cell death compared to each reagent alone. In vivo , DMAMCL(75 mg/kg or 100 mg/kg) inhibited tumor growth and prolonged survival of mice bearing xenograft RMS tumors (RD, RH18, RH30, RH41). Compared to treatment with DMAMCL or VCR, a combination of two reagents caused significant inhibition of tumor growth (RD, RH41), even after treatment termination. The expression of Bim increased at protein level after DMAMCL treatment both in vitro and in vivo. The expression of p-NF-κB(p65) had a transient increase and the generation of ROS increased after DMAMCL treatment in vitro. Transfection of Bim siRNA into RMS cells blocked the DMAMCL-induced increase of Bim and partially attenuated the DMAMCL-induced cell death. Conclusion DMAMCL had an anti-tumor growth effect in vitro and in vivo that potentially mediated by Bim, NF-κB pathway and ROS. A combination of DMAMCL with chemotherapeutic drugs significantly increased the treatment efficacy. Our study supports further clinical evaluation of DMAMCL in combination with conventional chemotherapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1107-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

Hua

et al. 2019

J Exp Clin Cancer Res

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“…The expression of NF-κB in HSCs is low, while it is significantly over expressed in LSCs (36). Therefore, NF-κB could distinguish HSCs and LSCs, and may serve as a potential therapeutic target for the selective elimination of LSCs sparing HSCs (37,38).…”

Section: The Transcription Factors Of Lscs In Amlmentioning

confidence: 99%

“…DMAMCL (ACT001) was able to eliminate LSCs by inhibiting the activity of NF-κB. ACT001 was in clinical trial in Australia (36,40).…”

Section: The Transcription Factors Of Lscs In Amlmentioning

confidence: 99%

The biomarkers of leukemia stem cells in acute myeloid leukemia

Ding¹,

Gao²,

Zhang³

2017

Stem Cell Investig.

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“…The expression of NF-kB in normal hematopoietic stem cells was low, while it was overexpressed significantly in leukemia stem cells [ 39 ]. Therefore, the expression and activity inhibition of NF-kB could be a potential therapeutic target for targeting leukemia stem cell.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of NF-kB and NF-kB-regulated proteins such as p65, Bcl-2, XIAP, and FLIP played important roles in cell apoptosis. It was reported that parthenolide and micheliolide, with chemically reactive alpha-beta unsaturated lactone moiety, were able to covalently bind to proteins via the Michael acceptor and eliminate leukemia stem cell by inhibiting the activity of NF-kB [ 17 , 19 , 39 ]. We speculated that compounds with alpha-beta unsaturated lactone moiety might share some common protein targets.…”

Section: Discussionmentioning

confidence: 99%

Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells

Ding

Gao

et al. 2016

J Hematol Oncol

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BackgroundThe poor outcomes for patients diagnosed with acute myeloid leukemia (AML) are largely attributed to leukemia stem cells (LSCs) which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity.MethodsThe aim of the present study was to identify alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of alantolactone in vitro and in vivo.ResultsThe present study is the first to demonstrate that alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C), alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-alantolactone, a water-soluble prodrug of alantolactone, could suppress tumor growth in vivo.ConclusionsBased on these results, we propose that alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0327-5) contains supplementary material, which is available to authorized users.

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Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells

Cited by 46 publications

References 33 publications

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

The biomarkers of leukemia stem cells in acute myeloid leukemia

Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells

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