Noack, Katrin and Mahendrarajah, Nisintha and Hennig, Dorle and Schmidt, Luisa and Grebien, Florian and Hildebrand, Dagmar and Christmann, Markus and Kaina, Bernd and Sellmer, Andreas and Mahboobi, Siavosh and Kubatzky, Katharina and Heinzel, Thorsten and Kraemer, Oliver H. (2017) Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells. ARCHIVES OF TOXICOLOGY, 91 (5). pp. 2191-2208. ISSN 0340-5761, 1432-0738
Full text not available from this repository. (Request a copy)Abstract
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), panHDACi (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-kappa B, 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 naive and maturated APL cells.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; NF-KAPPA-B; CCAAT/ENHANCER-BINDING-PROTEINS; DNA-DAMAGE RESPONSE; PML-RAR-ALPHA; CLASS-I HDAC; VALPROIC ACID; MULTIPLE-MYELOMA; C/EBP-BETA; APL; ATRA; DNA damage; HDAC; HDACi; Histone acetylation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:10 |
| Last Modified: | 18 Feb 2019 13:23 |
| URI: | https://pred.uni-regensburg.de/id/eprint/978 |
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