The Class IIA Histone Deacetylase (HDAC) Inhibitor TMP269 Downregulates Ribosomal Proteins and Has Anti-Proliferative and Pro-Apoptotic Effects on AML Cells.

Autor: Urwanisch L; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Unger MS; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Sieberer H; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Dang HH; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Neuper T; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Regl C; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Vetter J; Bioinformatics Research Group, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg im Muehlkreis, Austria., Schaller S; Bioinformatics Research Group, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg im Muehlkreis, Austria., Winkler SM; Bioinformatics Research Group, University of Applied Sciences Upper Austria, Softwarepark 11, 4232 Hagenberg im Muehlkreis, Austria., Kerschbamer E; Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via A. Volta 21, 39100 Bolzano, Italy., Weichenberger CX; Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via A. Volta 21, 39100 Bolzano, Italy., Krenn PW; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Luciano M; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Pleyer L; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria.; IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University, 5020 Salzburg, Austria.; Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020 Salzburg, Austria., Greil R; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria.; IIIrd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University, 5020 Salzburg, Austria.; Salzburg Cancer Research Institute with Laboratory of Immunological and Molecular Cancer Research and Center for Clinical Cancer and Immunology Trials, 5020 Salzburg, Austria., Huber CG; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Aberger F; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria., Horejs-Hoeck J; Department of Biosciences and Medical Biology, University of Salzburg, 5020 Salzburg, Austria.; Cancer Cluster Salzburg (CCS), 5020 Salzburg, Austria.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Feb 07; Vol. 15 (4). Date of Electronic Publication: 2023 Feb 07.
DOI: 10.3390/cancers15041039
Abstrakt: Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by altered myeloid progenitor cell proliferation and differentiation. As in many other cancers, epigenetic transcriptional repressors such as histone deacetylases (HDACs) are dysregulated in AML. Here, we investigated (1) HDAC gene expression in AML patients and in different AML cell lines and (2) the effect of treating AML cells with the specific class IIA HDAC inhibitor TMP269, by applying proteomic and comparative bioinformatic analyses. We also analyzed cell proliferation, apoptosis, and the cell-killing capacities of TMP269 in combination with venetoclax compared to azacitidine plus venetoclax, by flow cytometry. Our results demonstrate significantly overexpressed class I and class II HDAC genes in AML patients, a phenotype which is conserved in AML cell lines. In AML MOLM-13 cells, TMP269 treatment downregulated a set of ribosomal proteins which are overexpressed in AML patients at the transcriptional level. TMP269 showed anti-proliferative effects and induced additive apoptotic effects in combination with venetoclax. We conclude that TMP269 exerts anti-leukemic activity when combined with venetoclax and has potential as a therapeutic drug in AML.
Databáze: MEDLINE
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