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The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia

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Title: The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia
Authors: Wellbrock, Jasmin, Behrmann, Lena, Muschhammer, Jana, Modemann, Franziska, Khoury, Kais, Brauneck, Franziska, Bokemeyer, Carsten, Campeau, Eric, Fiedler, Walter
Source: Ann Hematol
Publisher Information: Springer Science and Business Media LLC, 2021.
Publication Year: 2021
Subject Terms: 0301 basic medicine, Antineoplastic Agents, Cell Cycle Proteins, 3. Good health, Leukemia, Myeloid, Acute, 03 medical and health sciences, Cell Line, Tumor, Hedgehog Proteins/metabolism [MeSH], Cell Line, Tumor [MeSH], Humans [MeSH], Transcription Factors/antagonists, BET inhibitor, Antineoplastic Agents/pharmacology [MeSH], GLI, Leukemia, Myeloid, Acute/metabolism [MeSH], Cell Cycle Proteins/antagonists, Original Article, Acute myeloid leukemia, Hedgehog, ZEN-3365, Signal Transduction/drug effects [MeSH], Cell Cycle Proteins/metabolism [MeSH], Leukemia, Myeloid, Acute/drug therapy [MeSH], Transcription Factors/metabolism [MeSH], Cell Proliferation/drug effects [MeSH], GANT-61, Humans, Hedgehog Proteins, Cell Proliferation, Signal Transduction, Transcription Factors
Description: Modern cancer therapies increased the survival rates of acute myeloid leukemia (AML) patients tremendously. However, the complexity of the disease and the identification of new targets require the adaptation of treatment protocols to reduce side effects and increase benefit for the patients. One key regulator of leukemogenesis and chemotherapy resistance in AML is the Hedgehog (HH) signaling pathway. It is deregulated in numerous cancer entities and inhibition of its downstream transcription factors GLI translates into anti-leukemic effects. One major regulator of GLI is BRD4, a BET family member with epigenetic functions. We investigated the effect of ZEN-3365, a novel BRD4 inhibitor, on AML cells in regard to the HH pathway. We show that ZEN-3365 alone or in combination with GANT-61 reduced GLI promoter activity, cell proliferation and colony formation in AML cell lines and primary cells. Our findings strongly support the evaluation of the BRD4 inhibitor ZEN-3365 as a new therapeutic option in AML.
Document Type: Article
Other literature type
Language: English
ISSN: 1432-0584
0939-5555
DOI: 10.1007/s00277-021-04602-z
Access URL: https://link.springer.com/content/pdf/10.1007/s00277-021-04602-z.pdf
https://pubmed.ncbi.nlm.nih.gov/34333666
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592969
https://pubmed.ncbi.nlm.nih.gov/34333666/
https://link.springer.com/article/10.1007/s00277-021-04602-z
https://fis-uke.de/portal/en/publications/the-bet-bromodomain-inhibitor-zen3365-targets-the-hedgehog-signaling-pathway-in-acute-myeloid-leukemia(74f7f56e-c423-46e2-8236-d3c0609ff9d5).html
https://link.springer.com/content/pdf/10.1007/s00277-021-04602-z.pdf
https://repository.publisso.de/resource/frl:6447809
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) .
Accession Number: edsair.doi.dedup.....a5031ff37d4dd0c1881fe3fca4bdd9fd
Database: OpenAIRE
Description
Abstract:Modern cancer therapies increased the survival rates of acute myeloid leukemia (AML) patients tremendously. However, the complexity of the disease and the identification of new targets require the adaptation of treatment protocols to reduce side effects and increase benefit for the patients. One key regulator of leukemogenesis and chemotherapy resistance in AML is the Hedgehog (HH) signaling pathway. It is deregulated in numerous cancer entities and inhibition of its downstream transcription factors GLI translates into anti-leukemic effects. One major regulator of GLI is BRD4, a BET family member with epigenetic functions. We investigated the effect of ZEN-3365, a novel BRD4 inhibitor, on AML cells in regard to the HH pathway. We show that ZEN-3365 alone or in combination with GANT-61 reduced GLI promoter activity, cell proliferation and colony formation in AML cell lines and primary cells. Our findings strongly support the evaluation of the BRD4 inhibitor ZEN-3365 as a new therapeutic option in AML.
ISSN:14320584
09395555
DOI:10.1007/s00277-021-04602-z