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Tytuł pozycji:

A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells.

Tytuł :
A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells.
Autorzy :
Lu X; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Yan G; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Dawood M; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany; Department of Molecular Biology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum, Sudan.
Klauck SM; Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), Heidelberg, Germany.
Sugimoto Y; Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
Klinger A; MicroCombiChem GmbH, 65203 Wiesbaden, Germany.
Fleischer E; MicroCombiChem GmbH, 65203 Wiesbaden, Germany.
Shan L; The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Efferth T; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: .
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Źródło :
Biochemical pharmacology [Biochem Pharmacol] 2021 Jul 12, pp. 114677. Date of Electronic Publication: 2021 Jul 12.
Publication Model :
Ahead of Print
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
Contributed Indexing :
Keywords: Apoptosis; Histone deacetylases; Leukemia; Multidrug resistance; P-glycoprotein; Zebrafish
Entry Date(s) :
Date Created: 20210715 Latest Revision: 20210715
Update Code :
20210716
DOI :
10.1016/j.bcp.2021.114677
PMID :
34265280
Czasopismo naukowe
New and potent agents that evade multidrug resistance (MDR) and inhibit epigenetic modifications are of great interest in cancer drug development. Here, we describe that a moniliformin derivative (IUPAC name: 3-(naphthalen-2-ylsulfanyl)-4-{[(2Z)-1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene]methyl}cyclobut-3-ene-1,2-dione; code: MCC1381) bypasses P-gp-mediated MDR. Using transcriptomics, we identified a large number of genes significantly regulated in response to MCC1381, which affected the cell cycle and disturbed cellular death and survival. The potential targets of MCC1381 might be histone deacetylases (HDACs) as predicted by SwissTargetPrediction. In silico studies confirmed that MCC1381 presented comparable affinity with HDAC1, 2, 3, 6, 8 and 11. Besides, the inhibition activity of HDACs was dose-dependently inhibited by MCC1381. Particularly, a strong binding affinity was observed between MCC1381 and HDAC6 by microscale thermophoresis analysis. MCC1381 decreased the expression of HDAC6, inversely correlated with the increase of acetylated HDAC6 substrates, acetylation p53 and α-tubulin. Furthermore, MCC1381 arrested the cell cycle at the G 2 /M phase, induced the generation of reactive oxygen species and collapse of the mitochondrial membrane potential. MCC1381 exhibited in vivo anti-cancer activity in xenografted zebrafish. Collectively, MCC1381 extended cytotoxicity towards P-gp-resistant leukemia cancer cells and may act as a pan-HDACs inhibitor, indicating that MCC1381 is a novel candidate for cancer therapy.
(Copyright © 2021. Published by Elsevier Inc.)

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