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Life Sciences May 2020Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic...
AIMS
Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms.
MAIN METHODS
MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects.
KEY FINDINGS
Our results demonstrated that SB939 at 0.5-1 μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models.
SIGNIFICANCE
Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.
Topics: Animals; Antigens, CD; Antineoplastic Agents; Benzimidazoles; Breast Neoplasms; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Interleukin-6; Lung Neoplasms; Mice; Mice, Nude; Repressor Proteins; STAT3 Transcription Factor; Signal Transduction; Tumor Burden; Vimentin; Xenograft Model Antitumor Assays
PubMed: 32109485
DOI: 10.1016/j.lfs.2020.117469 -
Biomedicines Jan 2020Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and... (Review)
Review
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
PubMed: 32019149
DOI: 10.3390/biomedicines8020022 -
Cancers Nov 2019Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid... (Review)
Review
Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.
PubMed: 31739588
DOI: 10.3390/cancers11111794 -
Journal of Cell Science Oct 2019Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small...
Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβ-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene () in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.
Topics: Cell Line; Down-Regulation; Fibroblasts; Histone Deacetylases; Humans; Lung; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Promoter Regions, Genetic; Pulmonary Fibrosis; Transforming Growth Factor beta
PubMed: 31527052
DOI: 10.1242/jcs.233486 -
British Journal of Haematology Feb 2020Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and...
A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy.
Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.
Topics: Aged; Aged, 80 and over; Benzimidazoles; Bone Marrow; Drug Therapy, Combination; Female; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Myelodysplastic Syndromes
PubMed: 31468521
DOI: 10.1111/bjh.16173 -
Chemical Biology & Drug Design Aug 2019A series of compounds similar to Pracinostat that contained benzimidazole ring and N-hydroxyacrylamide attached at 5- or 6-position were designed, synthesized, and...
A series of compounds similar to Pracinostat that contained benzimidazole ring and N-hydroxyacrylamide attached at 5- or 6-position were designed, synthesized, and evaluated as HDAC inhibitors. It was interesting to find that the corresponding derivative 1 with N-hydroxyacrylamide attached at 5-position was a potent HDAC inhibitor while the others at 6-position were not. This is the first time to demonstrate the position difference plays important role in the HDAC inhibitory activities of the cinnamic hydroxamates.
Topics: Benzimidazoles; HeLa Cells; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans
PubMed: 30932330
DOI: 10.1111/cbdd.13527