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), 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.
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Acknowledgements
We thank Anna Frumkina, ITOX Mainz, for help with the comet assay. This work was supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1002, the Wilhelm Sander-Foundation (#2010.078.2 to OHK), the Deutsche Krebshilfe (#110125 and #110909 to OHK), the Deutsche Forschungsgemeinschaft (#KR2291/4-1 and #KR2291/5-1 to OHK; MA2183/1-1 to SM), and startup grants from the UM Mainz and the NMFZ Mainz (to OHK). LS is the recipient of a DOC fellowship of the Austrian Academy of Sciences. Work in the laboratory of FG is supported by the ERC Starting Grant ONCOMECHAML.
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204_2016_1878_MOESM2_ESM.tif
Flow cytometry analyses of PI-stained NB4 cells. a Cells were treated for 48 h with 1 µM ATRA, and/or SAHA for 24 h with the indicated concentrations (mean + SEM, n = 3–4). b Cells were treated for 48 h with 1 µM ATRA, and/or with 5 µM MS-275 (MS) and 1 µM Marbostat-100 (Marb) for 24 h; n = 5. Same samples as shown in Fig. 1d. c Cells were treated with 1 µM ATRA for 48 h and/or 24 h FK228 (FK) with the indicated concentrations; n = 3–6. Same samples as shown in Fig. 1e. d Cells were stimulated for the indicated times with 1 µM ATRA, 5 µM MS-275, or 100 nm LBH589; n = 4 (TIFF 4625 kb)
204_2016_1878_MOESM3_ESM.tif
Analysis of STAT1 phosphorylation and expression. a NB4 cells were treated for the indicated times with 1.5 mM valproic acid and 1 µM ATRA. After an intracellular p-Tyr 701 STAT1 stain, the mean fluorescence was quantified by FACS analysis; n = 1. b NB4 cells were treated with 1,5-5 mM VPA for 24 h. Whole cell extracts were analyzed by Western blot for STAT1, acetyl-histone H3 (ac-H3), and acetyl-histone H4 (ac-H4); NF-κB p65 was tested as an additional control protein; Ctrl, untreated; β-actin, loading control; n = 3 (TIFF 4747 kb)
204_2016_1878_MOESM4_ESM.tif
Immunoblot analyses for cleaved caspase-3. a NB4 cells were treated for the indicated times with cytokines (1000 U IFN-α or 50 ng/ml TNF-α) and HDACi (5 mM VPA or 5 µM MS-275 (MS)); n = 3. The same cells as in 2 h were used. b Same as in a but with a 30-min pre-incubation with cytokines. The same cells as in 2i were used (TIFF 4682 kb)
204_2016_1878_MOESM5_ESM.tif
Apoptosis after HDACi treatment. a NB4 cells were treated with 2 µM MS-275, 30 nM LBH589, or 5 nM FK228 for 24–48 h; Ctrl, untreated. Cell death was measured by flow cytometry after Annexin V/PI staining. Representative dot plots are shown. b Quantification of cell death distinguished in early apoptotic (Annexin V +/PI-) and late apoptotic/necrotic (Annexin V +/PI +) cell populations. n = 3 ± SD; two-way ANOVA (Bonferroni’s multiple comparisons test); **P ≤ 0,01; ****P ≤ 0,0001. Statistical significance was determined with the GraphPad Prism 6 software (TIFF 6005 kb)
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Noack, K., Mahendrarajah, N., Hennig, D. et al. Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells. Arch Toxicol 91, 2191–2208 (2017). https://doi.org/10.1007/s00204-016-1878-5
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DOI: https://doi.org/10.1007/s00204-016-1878-5