Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cellsReport as inadecuate




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Journal of Hematology and Oncology

, 9:93

First Online: 22 September 2016Received: 26 July 2016Accepted: 16 September 2016DOI: 10.1186-s13045-016-0327-5

Cite this article as: Ding, Y., Gao, H., Zhang, Y. et al. J Hematol Oncol 2016 9: 93. doi:10.1186-s13045-016-0327-5

Abstract

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.

KeywordsAlantolactone Acute myeloid leukemia stem cells KG1a Apoptosis Abbreviations7-AAD7-Aminoactinomycin

ADRAdriamycin

Ara-CCytosine arabinoside

CFUsColony-forming units

DMAPTDimethyl-aminoparthenolide

HNE4-Hydroxynonenal

HSCsHematopoietic stem cells

LSCsLeukemia stem cells

MCLMicheliolide

MRDMinimal residual disease

MTTMethyl thiazolyl tetrazolium

PTLParthenolide

SLSesquiterpene lactone

TDZD-84-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione

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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Author: Yahui Ding - Huier Gao - Yu Zhang - Ye Li - Neil Vasdev - Yingdai Gao - Yue Chen - Quan Zhang

Source: https://link.springer.com/







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