Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.720
Filtrar
1.
Anticancer Res ; 41(9): 4353-4364, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475055

RESUMO

BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-tumor agent. However, resistance to TRAIL has been reported in a number of clinical trials. In this study, we investigated the molecular mechanisms by which a novel histone deacetylase (HDAC) inhibitor, CBUD-1001, sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. MATERIALS AND METHODS: Apoptotic cell death induced by CBUD-1001 and/or TRAIL was assessed on human CRC cells using the MTT assay, FACS analysis and nuclei staining. The involved molecular mechanisms were explored through western blotting analysis. RESULTS: We demonstrated that combined with CBUD-1001, TRAIL significantly enhanced TRAIL-induced apoptosis in CRC cells via mitochondria-mediated pathways. We also found that hyper-acetylation of histone by CBUD-1001 treatment leads to up-regulation of death receptor (DR) 5 in a dose- and time-dependent manner. Furthermore, we identified that enhanced sensitivity to TRAIL by combination with CBUD-1001 depends on the MAPK/CHOP axis, being a key mediator of DR5. CONCLUSION: A novel HDAC inhibitor CBUD-1001 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and that CBUD-1001 and TRAIL combination treatment offers an effective strategy to overcome TRAIL resistance in CRC cells.


Assuntos
Neoplasias Colorretais/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos
2.
Zhonghua Zhong Liu Za Zhi ; 43(8): 821-826, 2021 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-34407585

RESUMO

Objective: To analyze the expression pattern, mechanism and clinical significance of melanoma-associated antigen-C2 (MAGE-C2) in tumor-free breast specimens, breast benign disease specimens and breast cancer specimens. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to investigate the expressions of MAGE-C2 in 60 tumor-free breast specimens, 60 breast benign disease specimens and 60 breast cancer specimens. The correlation of MAGE-C2 expression with clinicopathological parameters and prognosis of breast cancer patients were analyzed. The expression of MAGE-C2 was also detected by RT-PCR in breast cancer cell MCF-7 and MDA-MB-231 treated with DNA methylase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) and histone deacetylase inhibitor trichostatin A (TSA). Results: The positive expression rates of MAGE-C2 mRNA and protein were 61.7% (37/60) and 58.3% (35/60) in breast cancer specimens, respectively, while negative expressed in breast and begin disease specimens. MAGE-C2 protein expression was associated with tumor grade, histological type and blood vessel invasion of breast cancer patients (P<0.05). The incidence of recurrence-free survival of patients with positive MAGE-C2 expression were lower than that of patients with negative MAGE-C2 expression (P<0.05). Multivariate Cox regression analysis showed that the clinical stage (P<0.01), lymph node metastasis (P<0.05) and MAGE-C2 expression (P<0.05) were the independent prognostic factors of breast cancer patients. The MAGE-C2 mRNA was not observed in the control and TSA treated breast cancer cells while upregulated in the 5-aza-CdR treated cells. Besides, 5-aza-CdR combined with TSA further enhanced MAGE-C2 mRNA level in breast cancer cells (P<0.05). Conclusions: MAGE-C2 is one of the tumor-specific antigen and its expression is related with the poor prognosis of breast cancer patients. DNA methylation and histone acetylation may be an important regulation mechanism of MAGE-C2 gene expression.


Assuntos
Neoplasias da Mama , Melanoma , Azacitidina/farmacologia , Neoplasias da Mama/genética , Decitabina/farmacologia , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos
3.
Medicine (Baltimore) ; 100(31): e26788, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397830

RESUMO

BACKGROUND: In this study, we evaluated the efficacy and safety of histone deacetylase inhibitors (HDACIs) in the treatment of renal cell carcinoma (RCC). METHODS: PubMed, EMBASE, the Cochrane Library, CNKI, and the Wanfang database were searched to retrieve studies describing the use of HDACIs for the treatment of RCC published between January 1, 2009, and January 1, 2021. Relevant studies were selected, and data were extracted. Then, a meta-analysis was performed using R 3.5.2 software. RESULTS: The results showed that the objective response rate (ORR) of HDACIs used to treat RCC was 26% [95% confidence interval (95% CI): 0.19∼0.34] and that the 1-year progression-free survival (PFS) rate was 29% (95% CI: 0.14∼0.59). The ORR and PFS rate of the combination group were better than those of the monotherapy group, and the ORR and PFS rate of the selective HDACI group were better than those of the pan-HDACI group. The incidences of neutropenia and thrombocytopenia were higher and the incidence of fatigue was lower in the selective HDACI group than in the pan-HDACI group. CONCLUSION: This study initially confirmed the efficacy and safety of HDACIs for the treatment of RCC. Due to the limitations of the included studies, more high-quality studies are needed to validate the conclusions.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Estadiamento de Neoplasias , Resultado do Tratamento
4.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445133

RESUMO

New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Receptores ErbB/antagonistas & inibidores , Células Hep G2 , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Linfoma/tratamento farmacológico , Linfoma/metabolismo
5.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445277

RESUMO

Breast cancer (BC) is the leading cause of death in women all over the world. Currently, combined chemotherapy with two or more agents is considered a promising anti-cancer tool to achieve better therapeutic response and to reduce therapy-related side effects. In our study, we demonstrated an antagonistic effect of cytostatic agent-cisplatin (CDDP) and histone deacetylase inhibitor: cambinol (CAM) for breast cancer cell lines with different phenotypes: estrogen receptor positive (MCF7, T47D) and triple negative (MDA-MB-231, MDA-MB-468). The type of pharmacological interaction was assessed by an isobolographic analysis. Our results showed that both agents used separately induced cell apoptosis; however, applying them in combination ameliorated antiproliferative effect for all BC cell lines indicating antagonistic interaction. Cell cycle analysis showed that CAM abolished cell cycle arrest in S phase, which was induced by CDDP. Additionally, CAM increased cell proliferation compared to CDDP used alone. Our data indicate that CAM and CDDP used in combination produce antagonistic interaction, which could inhibit anti-cancer treatment efficacy, showing importance of preclinical testing.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino , Antagonismo de Drogas , Inibidores de Histona Desacetilases/farmacologia , Modelos Biológicos , Naftalenos , Pirimidinonas , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Cisplatino/antagonistas & inibidores , Cisplatino/farmacologia , Feminino , Humanos , Células MCF-7 , Naftalenos/antagonistas & inibidores , Naftalenos/farmacologia , Pirimidinonas/antagonistas & inibidores , Pirimidinonas/farmacologia
6.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299636

RESUMO

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.


Assuntos
Movimento Celular , Células Epiteliais/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Luz , Neovascularização Retiniana/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Células Epiteliais/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Células HeLa , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/química , Humanos , Masculino , Camundongos , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/patologia , Epitélio Pigmentado da Retina/irrigação sanguínea , Epitélio Pigmentado da Retina/patologia
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(8): 693-701, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34236029

RESUMO

Objective To investigate the role of HDAC6 in the interference of Legionella pneumophila on the autophagy of macrophages and its mechanism. Methods RAW264.7 macrophages were treated with 10 µmol/L, 5 µmol/L, and 2.5 µmol/L tubastatin A (TubA). CCK-8 assay was used to detect the proliferative activity of RAW264.7 macrophages, and the half maximal inhibitory concentration (IC50) of TubA was determined. A model of RAW264.7 macrophages infected with Legionella pneumophila was established and divided into TubA free groups (further divided into cell control group, inactivated bacteria group, and live bacteria group) and TubA treatment groups (10 µmol/L, 5 µmol/L, 2.5 µmol/L, each further divided into cell control group, inactivated bacteria group, and live bacteria group). The cells were collected at 6, 12, 24, and 48 h after Legionella pneumophila infection. The bacterial proliferation assay was conducted to detect the proliferation of Legionella pneumophila in RAW264.7 macrophages; RAW264.7 macrophages were transfected with pmCherry-C1-EGFP-LC3B plasmid to detect autophagic flux changes in each group; real-time quantitative PCR and Western blot were used respectively to detect the mRNA and protein expression levels of histone deacetylase 6 (HDAC6), sequestosome 1(SQSTM1/P62), microtubule associated protein 1 light chain 3 (LC3), α-tubulin, valosin containing protein (p97/VCP), heat shock protein 90 (HSP90), HSP70, heat shock transcription factor 1 (HSF1), and filamentous actin (F-actin). Results IC50 of TubA was 50 µmol/L. Compared with those in the RAW264.7 normal control group, the proliferation of Legionella pneumophila in mouse macrophages was significantly reduced after the addition of TubA. In the groups without the HDAC6 inhibitor, the live bacteria group had a stronger inhibiting effect on autophagic flux than the inactivated bacteria group compared with the normal control group. In the TubA groups with the HDAC6 inhibitor, the green fluorescence bright spots decreased and the autophagic flux increased in the live bacteria group. After the RAW264.7 macrophages were treated with inactivated and live Legionella pneumophila for 6, 12, 24, and 48 h, the mRNA and protein expression levels of HDAC6, α-tubulin, p97-VCP, and P62 decreased in the TubA group interfered with the Legionella pneumophila compared with the RAW264.7 normal control group. Conclusion The interference of Legionella pneumophila on the autophagy of macrophages is associated with the signal pathways of HDAC6/P62/LC3B and HDAC6/p97/HSF1.


Assuntos
Inibidores de Histona Desacetilases , Legionella pneumophila , Animais , Autofagia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos , Indóis , Camundongos
8.
Nat Commun ; 12(1): 4439, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290235

RESUMO

The α- and ß-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Inativação Gênica , Ativação Transcricional , Globinas zeta/genética , Acetilação , Animais , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos , Células Eritroides/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos , alfa-Globinas/genética
9.
Aging (Albany NY) ; 13(13): 17489-17498, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34232916

RESUMO

BACKGROUND AND PURPOSE: Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism. METHODS: The adipogenesis of 3T3-L1 cells was induced by stimulation with a differentiation cocktail (DMI) medium for 8 days. MTT assay was used to measure the cell viability and Oil Red O staining was used to evaluate the adipogenesis of 3T3-L1 cells. The total level of triglyceride and released glycerol were detected to evaluate the lipolysis during 3T3-L1 adipogenesis. The expression levels of Leptin, fatty acid-binding protein 4 (FABP4), and sterol regulatory element-binding protein (SREBP1C) were determined by qRT-PCR. qRT-PCR assay was utilized to detect the expression levels of PPARγ and C/EBPα in 3T3-L1 cells. A high-fat diet (HFD) was used to construct an obese mice model, followed by the treatment with TSA. HE staining was conducted to evaluate the pathological state of adipose tissues. Body weights and the weights of adipose tissues were recorded to evaluate the anti-obesity property of TSA. RESULTS: Firstly, the promoted lipid accumulation induced by DMI incubation was significantly reversed by the treatment with TSA in a dose-dependent manner. The elevated expression levels of Leptin, FABP4, SREBP1C, PPARγ, and C/EBPα induced by the stimulation with DMI incubation were dramatically inhibited by the introduction of TSA, accompanied by the upregulation of phosphorylated AMP-activated protein kinase (p-AMPK). Secondly, the inhibitory effect of TSA against the expression level of PPARγ and lipid accumulation was greatly abolished by an AMPK inhibitor. Lastly, the increased body weights and visceral adipocyte tissue weight, as well as the enlarged size of adipocytes induced by HFD were pronouncedly reversed by the administration of TSA. CONCLUSION: TSA inhibited adipogenesis in 3T3-L1 preadipocytes by activating the AMPK pathway.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Células 3T3-L1 , Tecido Adiposo/patologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Proteínas de Ligação a Ácido Graxo/genética , Glicerol/metabolismo , Leptina/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Obesos , Obesidade/genética , Triglicerídeos/metabolismo
10.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298911

RESUMO

Osteoarthritis (OA) is the most common articular degenerative disease characterized by chronic pain, joint inflammation, and movement limitations, which are significantly influenced by aberrant epigenetic modifications of numerous OA-susceptible genes. Recent studies revealed that both the abnormal activation and differential expression of histone deacetylases (HDACs) might contribute to OA pathogenesis. In this study, we investigated the chondroprotective effects of a marine-derived HDAC inhibitor, panobinostat, on anterior cruciate ligament transection (ACLT)-induced experimental OA rats. The intra-articular administration of 2 or 10 µg of panobinostat (each group, n = 7) per week from the 6th to 17th week attenuates ACLT-induced nociceptive behaviors, including secondary mechanical allodynia and weight-bearing distribution. Histopathological and microcomputed tomography analysis showed that panobinostat significantly prevents cartilage degeneration after ACLT. Moreover, intra-articular panobinostat exerts hypertrophic effects in the chondrocytes of articular cartilage by regulating the protein expressions of HDAC4, HDAC6, HDAC7, runt-domain transcription factor-2, and matrix metalloproteinase-13. The study indicated that HDACs might have different modulations on the chondrocyte phenotype in the early stages of OA development. These results provide new evidence that panobinostat may be a potential therapeutic drug for OA.


Assuntos
Ligamento Cruzado Anterior/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Panobinostat/farmacologia , Animais , Ligamento Cruzado Anterior/metabolismo , Lesões do Ligamento Cruzado Anterior/tratamento farmacológico , Lesões do Ligamento Cruzado Anterior/metabolismo , Doenças das Cartilagens/tratamento farmacológico , Doenças das Cartilagens/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Modelos Animais de Doenças , Masculino , Osteoartrite do Joelho/metabolismo , Dor/metabolismo , Ratos , Ratos Wistar , Suporte de Carga
11.
Nat Commun ; 12(1): 4319, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262032

RESUMO

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.


Assuntos
Antineoplásicos/uso terapêutico , DNA Helicases/deficiência , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Nucleares/deficiência , Fatores de Transcrição/deficiência , Animais , Antineoplásicos/farmacologia , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA Helicases/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fatores de Transcrição/metabolismo , Ativação Transcricional
12.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34073043

RESUMO

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3ß or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3ß/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3ß and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3ß/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Síndromes Epilépticas/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Histona Desacetilases , Neurônios/efeitos dos fármacos , Espasmos Infantis/tratamento farmacológico , Animais , Linhagem Celular , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/patologia
13.
Life Sci ; 281: 119765, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186043

RESUMO

AIMS: Deployment-related exposures to organophosphate (OP) compounds are implicated for Gulf War Illness (GWI) development in First GW veterans. However, reasons for the persistence of GWI are not fully understood. Epigenetic modifications to chromatin are regulatory mechanisms that can adaptively or maladaptively respond to external stimuli. These include DNA methylation and histone acetylation. DNA methylation changes have been reported in GWI but the role of histone acetylation in GWI has been less explored, despite its importance as an epigenetic mechanism for neurological disorders. MAIN METHODS: Male Sprague-Dawley rats were exposed to OP diisopropyl fluorophosphate (DFP, 0.5 mg/kg s.c., 5-d) and 6-m later brains were dissected for hippocampus. Western blotting, activity assays and chromatin immunoprecipitation (ChIP) were utilized for epigenetic analyses. Behavior was assessed using the Forced Swim Test (FST) and the Elevated Plus Maze (EPM). KEY FINDINGS: We observed a significant upregulation in HDAC1 protein along with a significant increase in HDAC enzyme activity in the hippocampus of DFP rats. A locus-specific ChIP study revealed decreases in H3K9ac at the brain derived neurotrophic factor (Bdnf) promoter IV coupled with a significant decrease in BDNF protein in DFP rat hippocampus. Treatment with HDAC inhibitor valproic acid reduced HDAC activity and decreased the FST immobility time in DFP rats. SIGNIFICANCE: Our research suggests that epigenetic alterations to histone acetylation pathways and decreased BDNF expression could represent novel mechanisms for GWI symptomatology and may provide new targets for developing effective drugs for GWI treatment.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Histonas/metabolismo , Isoflurofato/administração & dosagem , Acetilação , Animais , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Masculino , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Ácido Valproico/farmacologia
14.
Eur J Med Chem ; 222: 113569, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111829

RESUMO

Novel 5-pyridinyl-1,2,4-triazoles were designed as dual inhibitors of histone deacetylase 2 (HDAC2) and focal adhesion kinase (FAK). Compounds 5d, 6a, 7c, and 11c were determined as potential inhibitors of both HDAC2 (IC50 = 0.09-1.40 µM) and FAK (IC50 = 12.59-36.11 nM); 6a revealed the highest activity with IC50 values of 0.09 µM and 12.59 nM for HDAC2 and FAK, respectively. Compound 6a was superior to reference drugs vorinostat and valproic acid in its ability to inhibit growth/proliferation of A-498 and Caki-1 renal cancer cells. Further investigation proved that 6a strongly arrests the cell cycle at the G2/M phase and triggers apoptosis in both A-498 and Caki-1 cells. Moreover, the enhanced Akt activity that is observed upon chronic application of HDAC inhibitors was effectively suppressed by the dual HDAC2/FAK inhibitor. Finally, the high potency and selectivity of 6a towards HDAC2 and FAK proteins were rationalized by molecular docking. Taken together, these findings highlight the potential of 6a as a promising dual-acting HDAC2/FAK inhibitor that could benefit from further optimization.


Assuntos
Antineoplásicos/farmacologia , Quinase 1 de Adesão Focal/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzamidas/química , Benzamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 1 de Adesão Focal/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Triazóis/química , Células Tumorais Cultivadas
15.
J Med Chem ; 64(13): 8827-8869, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34161101

RESUMO

The acetylation of histone and non-histone proteins has been implicated in several disease states. Modulation of such epigenetic modifications has therefore made histone deacetylases (HDACs) important drug targets. HDAC3, among various class I HDACs, has been signified as a potentially validated target in multiple diseases, namely, cancer, neurodegenerative diseases, diabetes, obesity, cardiovascular disorders, autoimmune diseases, inflammatory diseases, parasitic infections, and HIV. However, only a handful of HDAC3-selective inhibitors have been reported in spite of continuous efforts in design and development of HDAC3-selective inhibitors. In this Perspective, the roles of HDAC3 in various diseases as well as numerous potent and HDAC3-selective inhibitors have been discussed in detail. It will surely open up a new vista in the discovery of newer, more effective, and more selective HDAC3 inhibitors.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Neoplasias/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores de Histona Desacetilases/química , Humanos , Neoplasias/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo
16.
J Enzyme Inhib Med Chem ; 36(1): 1387-1401, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34167419

RESUMO

Five pathways involving different ring structures led to generation of fourteen thienylbenzamides (7-20) which display the structure-activity relationships of class I HDAC inhibitors. All the synthesised compounds inhibit HDAC1 and HDAC2 selectively over other isoforms and many inhibit DLD1 and HCT116 cells more effectively than a parent compound. Compounds 8 and 16 inhibit HCT116 cells by activation of the apoptosis pathway.


Assuntos
Desenvolvimento de Medicamentos , Inibidores de Histona Desacetilases/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
17.
J Enzyme Inhib Med Chem ; 36(1): 1290-1312, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34187263

RESUMO

A series of thieno[2,3-d]pyrimidine-based hydroxamic acid hybrids was designed and synthesised as multitarget anti-cancer agents, through incorporating the pharmacophore of EGFR, VEGFR2 into the inhibitory functionality of HDAC6. Three compounds (12c, 15b and 20b) were promising hits, whereas (12c) exhibited potent VEGFR2 inhibition (IC50=185 nM), potent EGFR inhibition (IC50=1.14 µM), and mild HDAC6 inhibition (23% inhibition). Moreover, compound (15c) was the most potent dual inhibitor among all the synthesised compounds, as it exhibited potent EGFR and VEGFR2 inhibition (IC50=19 nM) and (IC50=5.58 µM), respectively. While compounds (20d) and (7c) displayed nanomolar selective kinase inhibition with EGFR IC50= 68 nM and VEGFR2 IC50= 191 nM, respectively. All of the synthesised compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumour cell lines. Additionally, molecular docking studies and ADMET studies were carried out to gain further insight into their binding mode and predict the pharmacokinetic properties of all the synthesised inhibitors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/química , Pirimidinas/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
18.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069280

RESUMO

The use of human dental pulp stromal cells (hDPSCs) has gained increasing attention as an alternative stem cell source for bone tissue engineering. The modification of the cells' epigenetics has been found to play an important role in regulating differentiation, with the inhibition of histone deacetylases 3 (HDAC3) being linked to increased osteogenic differentiation. This study aimed to induce epigenetic reprogramming using the HDAC2 and 3 selective inhibitor, MI192 to promote hDPSCs osteogenic capacity for bone regeneration. MI192 treatment caused a time-dose-dependent change in hDPSC morphology and reduction in viability. Additionally, MI192 successfully augmented hDPSC epigenetic functionality, which resulted in increased histone acetylation and cell cycle arrest at the G2/M phase. MI192 pre-treatment exhibited a dose-dependent effect on hDPSCs alkaline phosphatase activity. Quantitative PCR and In-Cell Western further demonstrated that MI192 pre-treatment significantly upregulated hDPSCs osteoblast-related gene and protein expression (alkaline phosphatase, bone morphogenic protein 2, type I collagen and osteocalcin) during osteogenic differentiation. Importantly, MI192 pre-treatment significantly increased hDPSCs extracellular matrix collagen production and mineralisation. As such, for the first time, our findings show that epigenetic reprogramming with the HDAC2 and 3 selective inhibitor MI192 accelerates the osteogenic differentiation of hDPSCs, demonstrating the considerable utility of this MSCs engineering approach for bone augmentation strategies.


Assuntos
Benzamidas/farmacologia , Polpa Dentária/citologia , Inibidores de Histona Desacetilases/farmacologia , Isoquinolinas/farmacologia , Osteogênese/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Benzamidas/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Histonas/metabolismo , Humanos , Isoquinolinas/administração & dosagem , Dente Serotino/citologia , Osteogênese/fisiologia , Células Estromais/metabolismo
19.
Commun Biol ; 4(1): 677, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083702

RESUMO

Immortalized erythroid cell lines are expected to be a promising source of ex vivo manufactured red blood cells (RBCs), however the induction of enucleation in these cell lines is inefficient at present. We utilized an imaging-based high-throughput system to identify chemical compounds that trigger enucleation of human erythroid cell lines. Among >3,300 compounds, we identified multiple histone deacetylase inhibitors (HDACi) inducing enucleated cells from the cell line, although an increase in membrane fragility of enucleated cells was observed. Gene expression profiling revealed that HDACi treatment increased the expression of cytoskeletal genes, while an erythroid-specific cell membrane protein, SPTA1, was significantly down-regulated. Restoration of SPTA1 expression using CRISPR-activation partially rescued the fragility of cells and thereby improved the enucleation efficiency. Our observations provide a potential solution for the generation of mature cells from erythroid cell lines, contributing to the future realization of the use of immortalized cell lines for transfusion therapies.


Assuntos
Núcleo Celular/efeitos dos fármacos , Eritrócitos/metabolismo , Células Eritroides/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Inibidores de Histona Desacetilases/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Eritrócitos/citologia , Células Eritroides/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Inibidores de Histona Desacetilases/isolamento & purificação , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Colloids Surf B Biointerfaces ; 205: 111903, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34144323

RESUMO

A combination of photodynamic therapy (PDT) and histone deacetylase inhibitor (HDACis) could potentiate single-mode anti-tumor activity of HDACis or PDT to inhibit tumor relapse and metastasis. However, poor solubility and heterogeneity in cellular uptake and tissue distribution hamper the dual mode antitumor effect. For a controlled drug release of photosensitizers and HDACis in cytoplasm, photosensitizer pyropheophorbide-a (Pyro) encapsulated in polymer polyethylene glycol-b-poly (asparaginyl-vorinostat) (simplified as Pyro@FPPS) are fabricated to achieve their lysosomal spatiotemporal synchronized release. With HDACis modeling PDT in vitro and in vivo, it seems that polymerized Vorinostat encapsulated photosensitizers significantly inhibited the tumor proliferation and metastasis by spatiotemporal synchronized drugs release, and Pyro@FPPS reported here reveals a promising prospect to exert drugs' synergistic effect in a spatiotemporal synchronized manner and can be an effective strategy to inhibit tumor growth, recurrence and metastasis in clinic.


Assuntos
Antineoplásicos , Fotoquimioterapia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Inibidores de Histona Desacetilases/farmacologia , Lisossomos , Fármacos Fotossensibilizantes/farmacologia , Vorinostat/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...