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, This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license

, Despite the discovery of tyrosine kinase inhibitors (TKIs) for the treatment of 23 breakpoint cluster region-Abelson (BCR-ABL) + cancers, patients with chronic myeloid 24 leukemia (CML) treated with TKIs develop resistances and severe adverse effects

, Combination treatments, especially with a histone deacetylase (HDAC)6 inhibitor (HDAC6i), diminish BCR-ABL expression. Here, we hypothesized that HDAC6i compound 28 7b could lead to BCR-ABL downregulation in CML cells and sensitize them to TKI treatments

, Results showed that the imatinib-7b combination caused a strong synergistic caspase-dependent 30 apoptotic cell death and drastically reduced the proportion of leukemia stem cells, whereas it 31 only moderately affected healthy cells. Ultimately, the combination significantly decreased 32 colony formation in a semisolid methylcellulose medium and tumor mass in xenografted 33 zebrafishes as compared to each compound alone. Mechanistically, the combination induced 34 BCR-ABL ubiquitination and downregulation followed by the disturbance of key proteins of 35 its downstream pathways

, Keywords: 4-hydroxybenzoic acid; tyrosine kinase inhibitor

, Chemical compounds studied in this article: imatinib (PubChem CID: 123596)

, 43 suberanilohydroxamic acid (SAHA; PubChem CID: 5311); tubacin (PubChem CID: 6675804)

Z. Pubchem and C. , , vol.5737

, PubChem CID: 92209272) 45 and cisplatin (PubChem CID: 441203)

, Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a 62 reciprocal translocation between long arms of chromosomes 9 and 22, where Abelson (ABL) 63 and breakpoint cluster region (BCR) genes are located

, The result of this translocation is the constitutively active tyrosine kinase BCR-ABL involved

, Since 2001, treatment with the first-generation tyrosine kinase inhibitor (TKI) imatinib 68 (Gleevec®) has largely improved the management of CML; nevertheless, many patients 69 develop resistance [3] notably due to the existence of CML leukemia stem cells (LSCs), vol.70

, From this perspective, histone deacetylase 77 (HDAC) inhibitors (HDACi) recently emerged as a promising family of drug candidates for 78 combination therapies in multiple cancer models [9, 10] and to enhance imatinib-induced CML 79 cell death [11]. Nonetheless, clinical trials revealed that inhibition of multiple HDACs 80 associates with adverse effects [12] so that the use of pan-HDACis needs reconsideration. 81 HDAC6 plays a critical role by deacetylating heat shock protein (HSP) 90?, which in 82 turn loses its chaperon function for client proteins, Since monotherapy is frequently associated with drug resistance development, the use 75 of combination therapies appears as an attractive approach to prevent drug resistance and 76 improve therapeutic options for CML

, MEG-01, and U-937 cells were obtained from the Deutsche Sammlung für, vol.562

. Mikroorganismen-und-zellkulturen, KBM-5 cells and an imatinib-103 resistant K-562 (K-562R) subline were gifts from Dr

, Catholic University of Seoul, respectively. Peripheral blood mononuclear cells (PBMCs) from

, were purified, and were induced to proliferate by a mitogen-107 cytokine cocktail supplement whose composition includes phytohemagglutinin

D. Millipore, The Netherlands) 109 as reported before, Germany) and interleukin, vol.2

, All cell models were maintained at 37°C in a humidified atmosphere containing 5% of 112 CO 2 in a culture medium containing 1% (v/v) of an antibiotic solution (streptomycin and 113 penicillin) and an antimycotic solution (Lonza, Verviers, Belgium) as well as 10% of heat-114 inactivated fetal bovine serum (FBS; Lonza). The cell lines K-562, MEG-01, and U-937 and 115 PBMCs were cultured in RPMI 1640 (Lonza), whereas KBM-5 cells were cultured in IMDM 116 (Lonza). The cell lines K-562R and KBM-5R were cultured in the same medium as the parental 117 cell line with a supplement: 0.8 and 1 µM imatinib, respectively. CD34 + cells were cultured in 118 the serum-free Stem Cell II culture medium

, Compound 7b was synthetized as previously described, vol.14

. Imatinib, suberanilohydroxamic acid (SAHA, vol.124

). Aldrich, Z. Zvad;-millipore, ). , and E. , VP-16; Sigma-Aldrich) were 126 dissolved in DMSO. Cisplatin (ONCO-Tain ® , Hospira, USA) was purchased as an injectable 127 solution. Unless specified otherwise

, Whole-cell lysates were prepared with 131 the Mammalian Protein Extraction Reagent, vol.18

, Thermo Fischer Scientific) supplemented 132 with a 1× protease inhibitor cocktail (Complete EDTA-free, Roche), 1× phosphatase inhibitor 133 cocktail

, Protein concentration was determined by the Bradford assay

, Western blots were carried out as described elsewhere [19] with primary antibodies against ?-136 tubulin (CP06; Calbiochem; lot number: 2760575), ?-actin (A5441, vol.138

S. C. Biotechnology, , 2002.

, Cell Signaling Technology

. Leiden, The Netherlands; lot number: 4), c-Abelson (c-abl

S. C. Biotechnology,

, 141 lot number: K0414), c-Myc, pp.51-1485

, BD Biosciences, pp.3-56053

, Santa Cruz Biotechnology

, Cell Signaling Technology; lot number:18), caspase 9 (9502; Cell Signaling 144 Technology; 8), Crk-like protein (CrkL; 3182, Cell Signaling Technology, vol.145, pp.1-8030

, Santa Cruz Biotechnology, 2732.

, Signaling Technology; lot number: 4), myeloid cell leukemia 1 (Mcl-1; 4572; Cell Signaling 147 Technology; lot number: 4), phospho (P)-CrkL (3181, Cell Signaling Technology, p.9

, 6 ) were transfected without DNA (mock) or with 5 µg of various FLAG-173 tagged plasmids causing overexpression of either wild-type or HDAC6 proteins mutated at the 174 first catalytic site (H216A), at the second one (H611A), vol.562

, Lipofectamine LTX with Plus Reagent

, Belgium) following the manufacturer's protocol. All HDAC6-containing plasmids were a gift 177 from Pr

, At 24 h post-transfection, the cells were resuspended in lysis 179 buffer (50 mM Tris-HCl pH 7.4, 1% of Igepal, 0.25% of sodium deoxycholate, 150 mM NaCl

S. Basel, and salmon sperm DNA and bovine serum albumin (Millipore), and protein 184 concentration was determined by the Bradford assay

, Immunoprecipitation procedures were carried out overnight at 4°C using 250 µg of the protein 186 extract and 5 µg of an antibody against FLAG (sc-807, Santa Cruz Biotechnology) and HDAC6, vol.187

, The samples were then divided in two fractions: one fraction was subjected to an in vitro 190 HDAC6 activity assay as described elsewhere [22], and the other fraction was incubated for 5

, Cell viability and concentration were determined by means of a semiautomated image-195 based cell analyzer (Cedex XS Innovatis

, The morphology of the cell nucleus was observed after staining with the DNA-specific

, Germany) and intercalating agent propidium 201 iodide (Sigma-Aldrich) by fluorescence microscopy by means of a Cell^M imaging station 202 from Olympus, dye Hoechst, vol.33342

, Apoptosis was evaluated by the detection of phosphatidylserine exposure and was 206 quantified using the Annexin V-Fluorescein Isothiocyanate (FITC) Apoptosis Detection Kit I 207 (BD Biosciences) following the manufacturer's protocol. Cell fluorescence was measured on a 208 FACS Calibur flow cytometer (BD Biosciences) and analyzed in Flowjo® software

, Caspase activities were measured using Caspase-Glo® 3/7, 8, and 9 Assays

. Leiden, The Netherlands) following the manufacturer's protocol. Luminescence was quantified 214 on an Orion microplate luminometer, ) with the Simplicity 215 software (CMMS Software Apps

, The gene expression microarray dataset E-MTAB-2594 of CD34 + /CD38 -cells isolated to the various groups: untreated, dasatinib-, imatinib-and nilotinib-treated

, The detection of ALDH activity in cells was carried out by the Aldefluor Assay 232 (Stemcell Technologies, Grenoble, France) according to the manufacturer's guidelines. The

, Cells (10 3 cells/mL) were seeded on a semisolid methylcellulose medium

, StemCell Technologies) supplemented with 10% heat inactivated FBS (Lonza) and 240 treated with the indicated compounds. Colonies were grown at 37°C in a humidified atmosphere 241 containing 5% of CO 2 for 10 days and were detected by adding 1 mg/mL of the 3-(4,5-242 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reagent (Sigma-Aldrich) using 243 the Gel Doc XR+ System, H4230

, Wild-type zebrafish (Danio rerio) were maintained according to Seoul National

, College of Pharmacy guidelines. Xenograft injections with K-562 cells pretreated

, For computational 253 analysis of public CML datasets, statistical significance was assessed using ANOVA followed 254 by the Kruskal-Wallis test. For all the other analyses, parametric or nonparametric one-way and 255 two-way ANOVA tests and t tests were conducted for statistical comparisons, GraphPad Prism 8.0.1 software

, To validate the clinical relevance of HDAC6 as a potential anti-leukemic target, we 261 analyzed the public gene expression microarray dataset E-MTAB-2594 of leukemia stem cells 262 (LSCs) isolated from primary human CML samples that were treated with various TKIs 263 [dasatinib (150 nM), nilotinib (5 µM) and imatinib (5 µM)] for up to 7 days. We pooled these 264 data into a unique TKI-treated group, p.6

, Effects of compound 7b on ?-tubulin and histone H4 acetylation levels after 6 h of 287 treatment. (B) Kinetic analysis of ?-tubulin and histone H4 acetylation levels in cells treated 288 with various concentrations of compound 7b. (C) Kinetic analysis of ubiquitinated (upper 289 panel) and total BCR-ABL levels

, Kinetic analysis of the action of compound 7b on BCR-ABL expression in KBM-5 and MEG-291 01 cells. DMSO (D) was used as solvent control and tubacin (2 µM for K-562 cells and 1.5 µM 292 for KBM-5 and MEG-01 cells

R. Hdaci, Blots are representative of at least three independent experiments, with 294 ?-actin, histone H1, Coomassie blue and ?-tubulin serving as loading controls

*. and *. ,

, The observed increase of ?-tubulin acetylation was time-dependent starting from 0.5 h 302 in K-562 cells and from 6 and 9 h in KBM-5 and MEG-01 cells, respectively (Figure 2B), These with Phe620 and Phe680, similarly to other HDACis with zebrafish HDAC6 327 structures

, Since the implication of both catalytic sites in HDAC6 deacetylase activity is not clear, 329 we transfected K-562 cells with plasmids expressing wild-type HDAC6 or catalytic mutants: 330 deficient in the first catalytic site (H216A), the second (H611A)

, Supplementary Figure S4D), and HDAC activity was measured after FLAG 332 immunoprecipitation (Supplementary Figure S4E)

, Fluor de Lys-H4-AcK16 (data not shown). Altogether, our results suggest that compound 7b

, We also compared the in silico drug-likeness properties of compound 7b and of the bona

, Lipinski's rule 343 of five and globally showed better drug-likeness parameters than tubacin (Table I), vol.344, pp.1021-1022

. Dmso, Viability was determined by Trypan blue staining of PBMCs, by analysis of 369 phosphatidylserine exposure in platelets, and by nuclear morphological analysis of proliferative 370 PBMCs and CD34 + cells. Histograms correspond to the mean ± SD of three independent 371 experiments. *, **, and ***

, The downregulation of BCR-ABL protein expression induced by compound 7b on CML cell viability and proliferation were studied (Supplementary Figure S7), and 379 concentrations inducing death of less than 20% of cells were selected for combination 380 treatments (i.e., 0.25 µM for K-562 and MEG-01 cells

, HDAC6is, 7b and tubacin

, to the mean ± SD of three independent experiments. *, **, and *** indicate p < 413 0.05, p < 0.01, and p < 0.001, respectively, versus control cells, and °°° denotes p < 0.001 (for 414 live and apoptotic cells). (F) An assay of ALDH activity in K-562 cells upon 48 h of exposure 415 to imatinib-HDAC6i combinations. The ALDH inhibitor diethylaminobenzaldehyde (DEAB) 416 was employed to distinguish cell subpopulations with low and high ALDH activity. DMSO (D) 417 was used as solvent control

. Remarkably, MEG-01 cells, compound 7b used alone or in combination with imatinib (50.5%) compared with compound 7b (49%) or imatinib alone (17.8%). Similarly, the 1321, pp.1322-1323

, Assessment of the effects of the imatinib-7b combination on the 468 viability of various non-proliferative and proliferative healthy-cell models after 48 h of 469 treatment. C+: positive control for phosphatidylserine exposure obtained by incubating platelets 470 for 5 minutes with 50% DMSO. Viability was determined by Trypan blue staining of PBMCs, 471 by analysis of phosphatidylserine exposure in platelets, and by nuclear morphological analysis 472 of proliferative PBMCs and CD34 + cells. Histograms correspond to the mean ± SD of three 473 independent experiments. * and ***, HDAC6i 7b in combination with imatinib presents differential toxicity against 466 CML cells and reduces the CML cell colony-forming potential and tumor growth in 467 xenografted zebrafishes. (A), vol.5

, MTT signal intensity are presented as the 477 mean ± SD of four independent experiments (lower panel). *, **, and *** indicate p < 0.05, p 478 < 0.01, and p < 0.001, respectively, versus control cells. (C) Evaluation of the influence of the 479 imatinib-7b combination on the tumor growth of imatinib-sensitive and resistant K-562 cells in 480 the xenografted-zebrafish model. Zebrafish pictures were taken by fluorescence microscopy 481 (upper panel). ** and ***

, 35 553 The robust and fast induction of ?-tubulin hyperacetylation without affecting histone 554 H4 acetylation in CML cell lines confirmed the previously reported 7b-mediated HDAC6 K-562 cells, compound 7b enhances BCR-ABL 557 ubiquitination followed by its protein degradation, 1999.

, 560 regulation of BCR-ABL degradation through HSP90? acetylation is well characterized for 561 additional HDACis targeting HDAC6 activity

, Moreover, the decrease in BCR-ABL protein expression induced by compound 7b is 563 more important with imatinib compared to either compound alone, leading to a drastic decrease 564 in BCR-ABL phosphorylation. Accordingly, imatinib-7b combination impairs the expression , the antiapoptotic Bcl-2 family member Mcl-1 is a downstream target of STAT5 and 568 BCR-ABL, known to be one of the key regulators of LSC self-renewal and consequently 569 performs a critical function in cancer survival and resistance

, Here, we also demonstrated that imatinib and generally TKIs decreased HDAC6 mRNA Bamodu et al. showing that HDAC6 is overexpressed in LSCs [43] could explain the, 2041.

, In addition, it has been demonstrated that the dual targeting of c-Myc and p53

, Concentrations of compound 7b used in this study may seem high in the current context 588 where researchers are working to develop compounds usable at nanomolar concentrations

, 589 nevertheless, so far, many approved anticancer drugs are used in the high micromolar range, 590 e.g., hydroxyurea, 5-fluorouracil

, It is noteworthy that imatinib-7b combination globally exerts better anticancer effects

, Although all CML cell lines have been 601 isolated from patients in blast crisis and express the 210-kDa BCR-ABL protein, they express 602 two BCR-ABL transcripts: e14a2 also called b3a2 in K-562 and KBM-5 cells, and e13a2 also, Surprisingly, both imatinib-HDAC6i combinations fail to trigger any synergistic 600 anticancer effects in two other tested CML cell lines, 2155.

, MEG-01 cells (from a man) in comparison with K-562 cells (from a woman). However, other influence of BCR-ABL transcript type on the response to imatinib treatment stays 613 unclear and needs further research

, In agreement with in vitro results, imatinib-7b combination reduced tumor formation of 618 imatinib-sensitive and -resistant K-562 cell xenografts in zebrafish model

D. G. Ml and . Were-;-télévie-luxembourg, Research at LBMCC was 625 supported by the "Recherche Cancer et Sang" foundation, the

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, Half-maximal effective concentration (EC 50 ) values were calculated from western-blot 830 quantitative values given in Supplementary Figure 5 and correspond to the mean of three 831 independent experiments. The values were determined in GraphPad Prism 8.0.1 software, vol.832, 2817.

, LD 50 ) 836 were calculated from the data presented in Figure 3A and Supplementary Figure 6 and 837 correspond to the mean ± SD of three independent experiments. The values were determined 838 with GraphPad Prism 8.0.1 software, Concentrations inhibiting 50% of cell growth (GI 50 ) and inducing 50% of cell death, vol.839, p.49, 2877.

I. V. Table, The selectivity ratio of the imatinib-7b combination against K-562 cancer cells

, The selectivity ratio was calculated as follows: the percentage of cell death induced by the 843 imatinib-7b combination in K-562 cells (relative to the control) divided by the percentage of 844 death among healthy cells induced by the imatinib-7b combination (relative to the control), 2937.

N. J. Porter, J. D. Osko, D. Diedrich, T. Kurz, J. M. Hooker et al., Christianson Histone Deacetylase 6-Selective Inhibitors and the Influence of Capping Groups on Hydroxamate-Zinc Denticity, J. Med. Chem, issue.61, pp.8054-8060, 2018.

M. K. Mackwitz, A. Hamacher, J. D. Osko, J. Held, A. Scholer et al., Multicomponent Synthesis and Binding Mode of Imidazo[1,2-a]pyridine-Capped Selective HDAC6 Inhibitors, Org. Lett, issue.20, pp.3255-3258, 2018.