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BBA Advances 2022A large body of work has shown that MYB acts as a master transcription regulator in hematopoietic cells and has pinpointed MYB as a potential drug target for acute...
A large body of work has shown that MYB acts as a master transcription regulator in hematopoietic cells and has pinpointed MYB as a potential drug target for acute myeloid leukemia (AML). Here, we have examined the MYB-inhibitory potential of the HDAC inhibitor LAQ824, which was identified in a screen for novel MYB inhibitors. We show that nanomolar concentrations of LAQ824 and the related HDAC inhibitors vorinostat and panobinostat interfere with MYB function in two ways, by inducing its degradation and inhibiting its activity. Reporter assays show that the inhibition of MYB activity by LAQ824 involves the MYB transactivation domain and the cooperation of MYB with co-activator p300, a key MYB interaction partner and driver of MYB activity. In AML cells, LAQ824-induced degradation of MYB is accompanied by expression of myeloid differentiation markers and apoptotic and necrotic cell death. The ability of LAQ824 to inhibit MYB activity is supported by the observation that down-regulation of direct MYB target genes and occurs without apparent decrease of MYB expression already after 2 h of treatment with LAQ824. Furthermore, ectopic expression of an activated version of MYB In HL60 cells counteracts the induction of myeloid differentiation by LAQ824. Overall, our data identify LAQ824 and related HDAC inhibitors as potent MYB-inhibitory agents that exert dual effects on MYB expression and activity in AML cells.
PubMed: 37082582
DOI: 10.1016/j.bbadva.2021.100034 -
Advanced Science (Weinheim,... Aug 2022Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a...
Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.
Topics: Autophagy; Cell- and Tissue-Based Therapy; Epigenesis, Genetic; Fetal Blood; Humans; Hydrogels; Neoplasm Recurrence, Local; Triple Negative Breast Neoplasms; Vorinostat
PubMed: 35712750
DOI: 10.1002/advs.202201271 -
Investigational New Drugs Jun 2020The majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2...
The majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2 inhibitors such as ruxolitinib have been shown to be clinically efficacious, the hematological toxicity and eventual drug resistance limit its use as monotherapy. Other gene mutations or dysregulation correlated with the disease phenotype and prognosis have been found to contribute to the complexity and heterogeneity of MPNs, giving rise to an increasing demand for combination therapies. Here, we combine ruxolitinib and the histone deacetylase inhibitor vorinostat as a rational combination strategy for MPNs. We tested the combination of ruxolitinib and vorinostat in cells with the JAK2V617F mutation, such as HEL cells, c-Kit cells from JAK2V617F transgenic mice and bone marrow mononuclear cells (BMMNCs) from patients with MPN. Our results showed significant synergistic effects of this combination strategy. Cotreatment with ruxolitinib and vorinostat synergistically induced apoptosis, cell cycle arrest and inhibition of the colony-forming capacity of HEL cells by attenuating the JAK/signal transducer and activator of transcription (STAT) and protein kinase-B (AKT) signaling pathways. In particular, cotreatment with ruxolitinib and vorinostat prevented the formation of large colonies of colony-forming unit-granulocyte/erythroid/macrophage/megakaryocytes (CFU-GEMMs) and colony-forming unit-granulocyte/macrophages (CFU-GMs) derived from the BMMNCs of patients with MPN. Taken together, these data provided preclinical evidence that the combination of ruxolitinib and vorinostat is a potential dual-target therapy for patients with MPN.
Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Drug Synergism; Histone Deacetylases; Humans; Janus Kinase 2; Macrophages; Mice, Transgenic; Mutation; Myeloid Progenitor Cells; Myeloproliferative Disorders; Neoplasms; Nitriles; Pyrazoles; Pyrimidines; STAT Transcription Factors; Signal Transduction; Vorinostat
PubMed: 31227936
DOI: 10.1007/s10637-019-00794-4 -
PloS One 2022The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic...
The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic cancer. In this study, we demonstrated that M344, an HDAC inhibitor, is efficacious against pancreatic cancer in vitro and in vivo, alone or with gemcitabine. By 24 hours post-treatment, M344 augments the population of pancreatic cancer cells in G1, and at a later time point (48 hours) it increases apoptosis. M344 inhibits histone H3 deacetylation and slows pancreatic cancer cell proliferation better than vorinostat, and it does not decrease the viability of a non-malignant cell line more than vorinostat. M344 also elevates pancreatic cancer cell major histocompatibility complex (MHC) class I molecule expression, potentially increasing the susceptibility of pancreatic cancer cells to T cell lysis. Taken together, our findings support further investigation of M344 as a pancreatic cancer treatment.
Topics: Cell Line, Tumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Pancreatic Neoplasms; Vorinostat
PubMed: 36126055
DOI: 10.1371/journal.pone.0273518 -
Clinical Lymphoma, Myeloma & Leukemia Mar 2021Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and...
INTRODUCTION
Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and efficacy of the histone deacetylase (HDAC) inhibitor vorinostat in combination with bortezomib and dexamethasone.
PATIENTS AND METHODS
Sixteen patients who had received a median of 1 prior treatment line received bortezomib subcutaneously 1.3 mg/m days 1, 4, 8, and 11; dexamethasone 20 mg orally days 1-2, 4-5, 8-9, and 11-12; vorinostat 400 mg orally days 1-4, 8-11, and 15-18 of a 21-day cycle. After receipt of a minimum of 3 cycles of therapy, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28-day cycle).
RESULTS
Overall response was 81.3%: complete response occurred in 4 of 16, very good partial response in 2 of 16, and partial response 7 of 16. Clinical benefit response rate was 100%; median progression-free survival was 11.9 months. A total of 75% patients experienced a dose reduction or stopped treatment as a result of intolerability.
CONCLUSION
Although toxicity and dose reductions were observed, this study demonstrates that the combination of vorinostat, bortezomib, and dexamethasone is effective in relapsed myeloma with good response rates, suggesting there is an ongoing rationale for further optimization of HDAC inhibitor-based combinations in the treatment of myeloma to improve tolerability and enhance efficacy.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bortezomib; Dexamethasone; Female; Histone Deacetylase Inhibitors; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Multiple Myeloma; Neoplasm Staging; Prognosis; Recurrence; Retreatment; Treatment Outcome; Vorinostat
PubMed: 33478922
DOI: 10.1016/j.clml.2020.11.019 -
Angewandte Chemie (International Ed. in... Feb 2024The spiro[3.3]heptane core, with the non-coplanar exit vectors, was shown to be a saturated benzene bioisostere. This scaffold was incorporated into the anticancer drug...
The spiro[3.3]heptane core, with the non-coplanar exit vectors, was shown to be a saturated benzene bioisostere. This scaffold was incorporated into the anticancer drug sonidegib (instead of the meta-benzene), the anticancer drug vorinostat (instead of the phenyl ring), and the anesthetic drug benzocaine (instead of the para-benzene). The patent-free saturated analogs obtained showed a high potency in the corresponding biological assays.
Topics: Benzene; Heptanes; Chemical Phenomena; Antineoplastic Agents
PubMed: 38251921
DOI: 10.1002/anie.202316557 -
Cells Aug 2022Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell...
Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HDAC inhibitors (HDACis) have been approved for clinical use in some T-cell malignancies. Still, the exact targets and mechanisms of HDAC inhibition in cancer are understudied. We isolated tumor cell lines from a transgenic mouse model of anaplastic large cell lymphoma (ALCL), a rare T-cell lymphoma, and abrogated HDAC activity by treatment with the HDACis Vorinostat and Entinostat or Cre-mediated deletion of . Changes in overall protein expression as well as histone and protein acetylation were measured following deletion or pharmacological inhibition using label-free liquid chromatography mass spectrometry (LC-MS/MS). We found changes in overall protein abundance and increased acetylation of histones and non-histone proteins, many of which were newly discovered and associated with major metabolic and DNA damage pathways. For non-histone acetylation, we mapped a total of 1204 acetylated peptides corresponding to 603 proteins, including chromatin modifying proteins and transcription factors. Hyperacetylated proteins were involved in processes such as transcription, RNA metabolism and DNA damage repair (DDR). The DDR pathway was majorly affected by hyperacetylation following HDAC inhibition. This included acetylation of H2AX, PARP1 and previously unrecognized acetylation sites in TP53BP1. Our data provide a comprehensive view of the targets of HDAC inhibition in malignant T cells with general applicability and could have translational impact for the treatment of ALCL with HDACis alone or in combination therapies.
Topics: Acetylation; Animals; Chromatography, Liquid; Histone Deacetylases; Histones; Hydroxamic Acids; Lymphoma, Large-Cell, Anaplastic; Mice; Tandem Mass Spectrometry
PubMed: 35954222
DOI: 10.3390/cells11152380 -
The AAPS Journal Aug 2021Bortezomib and vorinostat exhibit synergistic effects in multiple myeloma (MM) cells when given in sequence, and the purpose of this study was to evaluate the molecular...
Bortezomib and vorinostat exhibit synergistic effects in multiple myeloma (MM) cells when given in sequence, and the purpose of this study was to evaluate the molecular determinants of the interaction using a systems pharmacology approach. A Boolean network model consisting of 79 proteins and 225 connections was developed using literature information characterizing mechanisms of drug action and intracellular signal transduction. Network visualization and structural analysis were conducted, and model simulations were compared with experimental data. Critical biomarkers, such as pNFκB, p53, cellular stress, and p21, were identified using measures of network centrality and model reduction. U266 cells were then exposed to bortezomib (3 nM) and vorinostat (2 μM) as single agents or in simultaneous and sequential (bortezomib for first 24 h, followed by addition of vorinostat for another 24 h) combinations. Temporal changes for nine of the critical proteins in the reduced Boolean model were measured over 48 h, and cellular proliferation was measured over 96 h. A mechanism-based systems model was developed that captured the biological basis of a bortezomib and vorinostat sequence-dependent pharmacodynamic interaction. The model was further extended in vivo by linking in vitro parameter values and dynamics of p21, caspase-3, and pAKT biomarkers to tumor growth in xenograft mice reported in the literature. Network-based methodologies and pharmacodynamic principles were integrated successfully to evaluate bortezomib and vorinostat interactions in a mechanistic and quantitative manner. The model can be potentially applied to evaluate their combination regimens and explore in vivo dosing regimens.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; Humans; Mice; Models, Biological; Multiple Myeloma; Network Pharmacology; Protein Interaction Maps; Signal Transduction; Systems Analysis; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 34403034
DOI: 10.1208/s12248-021-00622-9 -
Chemical Biology & Drug Design Oct 2019Four compounds T1, T2, T3, and T4 were designed and synthesized as Vorinostat and Belinostat derivatives being the target water-soluble prodrugs. The water solubility of...
Four compounds T1, T2, T3, and T4 were designed and synthesized as Vorinostat and Belinostat derivatives being the target water-soluble prodrugs. The water solubility of Vorinostat derivatives, T1 and T2, exhibited 400- to 600-fold higher than that of Vorinostat, and Belinostat derivatives, T3 and T4, showed 600- to 750-fold higher than that of Belinostat. Four compounds were evaluated for their inhibitory activities against tumor cell lines HT-29 and Hut-78 in the absence or presence of β-D-glucuronidase. The inhibitory effects of T1 and T2 were comparable to Vorinostat in the presence of β-D-glucuronidase, but were higher than 10 μM in the absence of β-D-glucuronidase. Therefore, T1 and T2 are promising candidates for in vivo investigations with high potential to be the target water-soluble prodrugs. IC values of Belinostat derivatives T3 and T4 were not affected by β-D-glucuronidase, but T3 and T4 had the excellent cell proliferation inhibition on Hut-78.
Topics: Drug Screening Assays, Antitumor; HT29 Cells; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Neoplasms; Prodrugs
PubMed: 31155843
DOI: 10.1111/cbdd.13577 -
Toxicology Aug 2020Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects...
Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects on non-cancerous cells remain poorly understood. As genetic and epigenetic changes play a critical role in the pathogenesis of carcinogenesis, we investigated whether vorinostat induces genetic and epigenetic alterations in mouse bone marrow cells. Bone marrow cells were isolated 24 h following the last oral administration of vorinostat at the doses of 25, 50, or 100 mg/kg/day for five days (approximately equal to the recommended human doses). The cells were then used to assess clastogenicity and aneugenicity by the micronucleus test complemented by fluorescence in situ hybridization assay; DNA strand breaks, oxidative DNA strand breaks, and DNA methylation by the modified comet assay; apoptosis by annexin V/PI staining analysis and the occurrence of the hypodiploid DNA content; and DNA damage/repair gene expression by polymerase chain reaction (PCR) Array. The expression of the mRNA transcripts were also confirmed by real-time PCR and western blot analysis. Vorinostat caused structural chromosomal damage, numerical chromosomal abnormalities, DNA strand breaks, oxidative DNA strand breaks, DNA hypomethylation, and programed cell death in a dose-dependent manner. Furthermore, the expression of numerous genes implicated in DNA damage/repair were altered after vorinostat treatment. Accordingly, the genetic/epigenetic mechanism(s) of action of vorinostat may play a role in its carcinogenicity and support the continued study and development of new compounds with lower toxicity.
Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Marrow Cells; Chromosome Aberrations; Comet Assay; DNA Methylation; DNA Repair; Dose-Response Relationship, Drug; Down-Regulation; Male; Mice; Oxidative Stress; Vorinostat
PubMed: 32512035
DOI: 10.1016/j.tox.2020.152507