Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells
Autor: | Dagmar Hildebrand, Katharina F. Kubatzky, Bernd Kaina, Markus Christmann, Nisintha Mahendrarajah, Oliver H. Krämer, Siavosh Mahboobi, Florian Grebien, Katrin Noack, Dorle Hennig, Thorsten Heinzel, Luisa Schmidt, Andreas Sellmer |
---|---|
Jazyk: | angličtina |
Předmět: |
0301 basic medicine
Acute promyelocytic leukemia Pyridines Health Toxicology and Mutagenesis Retinoic acid Apoptosis Tretinoin Toxicology Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine HDAC Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Humans Cytotoxic T cell ATRA neoplasms Phosphorylated Histone H2AX Leukemia Cell Death biology Kinase Cell Cycle HDACi NF-kappa B General Medicine medicine.disease Molecular biology HDAC1 Histone Deacetylase Inhibitors APL STAT1 Transcription Factor 030104 developmental biology Histone Histone acetylation chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Benzamides CCAAT-Enhancer-Binding Proteins biology.protein Cancer research DNA damage Histone deacetylase DNA Damage |
Zdroj: | Archives of Toxicology Noack, K, Mahendrarajah, N, Hennig, D, Schmidt, L, Grebien, F, Hildebrand, D, Christmann, M, Kaina, B, Sellmer, A, Mahboobi, S, Kubatzky, K, Heinzel, T & Krämer, O H 2017, ' Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells ', Archives of Toxicology, vol. 91, no. 5, pp. 2191-2208 . https://doi.org/10.1007/s00204-016-1878-5 |
ISSN: | 1432-0738 0340-5761 |
DOI: | 10.1007/s00204-016-1878-5 |
Popis: | The treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) induces granulocytic differentiation. This process renders APL cells resistant to cytotoxic chemotherapies. Epigenetic regulators of the histone deacetylases (HDACs) family, which comprise four classes (I–IV), critically control the development and progression of APL. We set out to clarify the parameters that determine the interaction between ATRA and histone deacetylase inhibitors (HDACi). Our assays included drugs against class I HDACs (MS-275, VPA, and FK228), pan-HDACi (LBH589, SAHA), and the novel HDAC6-selective compound Marbostat-100. We demonstrate that ATRA protects APL cells from cytotoxic effects of SAHA, MS-275, and Marbostat-100. However, LBH589 and FK228, which have a superior substrate–inhibitor dissociation constant (Ki) for the class I deacetylases HDAC1, 2, 3, are resistant against ATRA-dependent cytoprotective effects. We further show that HDACi evoke DNA damage, measured as induction of phosphorylated histone H2AX and by the comet assay. The ability of ATRA to protect APL cells from the induction of p-H2AX by HDACi is a readout for the cytoprotective effects of ATRA. Moreover, ATRA increases the fraction of cells in the G1 phase, together with an accumulation of the cyclin-dependent kinase inhibitor p21 and a reduced expression of thymidylate synthase (TdS). In contrast, the ATRA-dependent activation of the transcription factors STAT1, NF-κB, and C/EBP hardly influences the responses of APL cells to HDACi. We conclude that the affinity of HDACi for class I HDACs determines whether such drugs can kill naïve and maturated APL cells. |
Databáze: | OpenAIRE |
Externí odkaz: |