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1.
Anticancer Res ; 40(1): 9-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892549

RESUMO

BACKGROUND/AIM: Inhibition of apoptosis is one of the hallmarks of cancer, and anti-apoptotic genes are often targets of genetic and epigenetic alterations. Cellular inhibitor of apoptosis 2 (cIAP2) has a role in degrading caspases by linking them to ubiquitin molecules, and is upregulated in triple-negative breast cancer (TNBC). Previous studies have demonstrated that cIAP2 may play a role in the epithelial-to-mesenchymal transition (EMT). MATERIALS AND METHODS: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, was administered to triple-negative breast cancer (TNBC) cells alone or in combination with epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor isolated from green tea. RESULTS: The compounds were able to decrease the expression of cIAP2 while increasing the expression of pro-apoptotic caspase 7. There were also changes in histone modifications, suggesting a role of epigenetic mechanisms in these changes in expression of cIAP2. These changes resulted in an increase in apoptosis. SAHA and EGCG were also capable of limiting TNBC cell migration across a fibronectin (FN) matrix. CONCLUSION: SAHA and EGCG reduce the metastatic potential of TNBC by inducing the apoptotic pathway.


Assuntos
Apoptose/efeitos dos fármacos , Proteína 3 com Repetições IAP de Baculovírus/genética , Catequina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Vorinostat/farmacologia , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Catequina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
2.
Cancer Sci ; 111(1): 112-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31675763

RESUMO

Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mTOR pathway. The HMG-CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP-activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat-induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study to report the beneficial combined effect of vorinostat and fluvastatin in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Fluvastatina/farmacologia , Neoplasias Renais/tratamento farmacológico , Vorinostat/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Renais/metabolismo , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
3.
Res Vet Sci ; 126: 207-212, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31610471

RESUMO

To explore the effect of epigenetic modification on the differentiation of goat adipose-derived stem cells in vitro, we used two common epigenetic modification inhibitors, trichostatin A and vorinostat, to treat cashmere goat adipose-derived stem cells and induce adipocyte differentiation. The results showed that trichostatin A and vorinostat changed the relative amounts of H3K9 acetylation and dimethylation in the upstream sequence of PPARG, increased peroxisome proliferator-activated receptor gamma (PPARG) transcription before differentiation and then promoted adipocyte differentiation, and regulated the expression of adipocyte-specific genes. We conclude that adipocyte differentiation is regulated dynamically by different histone modifications. The areas of acetylation and demethylation changed by trichostatin A and vorinostat are the basis for further research on the mechanism of PPARG promoter to regulate adipocytes differentiation and provide research theroies for using adipose-derived stem cells as donor to produce transgenic animals to improve meat quality improvement.


Assuntos
Adipogenia/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Cabras/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Vorinostat/farmacologia , Acetilação/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Animais , Metilação/efeitos dos fármacos , PPAR gama/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia
4.
Cell Physiol Biochem ; 53(1): 258-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31313541

RESUMO

BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells. METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells. RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells. CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.


Assuntos
Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Receptores da Transferrina , Antígenos CD/genética , Antígenos CD/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Células HEK293 , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Vorinostat/farmacologia , Xantonas/farmacologia
5.
Anticancer Res ; 39(7): 3579-3584, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262882

RESUMO

BACKGROUND/AIM: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK. MATERIALS AND METHODS: Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting. RESULTS: Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression. CONCLUSION: Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neuroblastoma/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vorinostat/farmacologia , Quinase do Linfoma Anaplásico/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Mutação , Proteína Proto-Oncogênica N-Myc/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo
6.
Cancer Sci ; 110(8): 2493-2506, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215139

RESUMO

Gallbladder cancer (GBC) is the most common malignancy of the bile duct and has a high mortality rate. Here, we demonstrated that BRD4 inhibitor JQ1 and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) synergistically inhibited the GBC cells in vitro and in vivo. Our results showed that cotreatment with JQ1 and SAHA significantly inhibited proliferation, cell viability and metastasis, and induced apoptosis and G2/M arrest in GBC cells, with only minor effects in benign cells. In vivo, tumor volumes and weights of GBC xenograft models were significantly decreased after treatment with JQ1 or SAHA; meanwhile, the cotreatment showed the strongest effect. Further study indicated that the above anticancer effects was associated with the downregulation of BRD4 and suppression of PI3K/AKT and MAPK/ERK pathways. These findings highlight JQ1 and SAHA as potential therapeutic agents and their combination as a promising therapeutic strategy for GBC.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Neoplasias da Vesícula Biliar/patologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Vorinostat/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Sensors (Basel) ; 19(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100944

RESUMO

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. In recent studies, the efficacy of suberoylanilide hydroxamic acid (SAHA) has been investigated for GBM. We explored the effects of two exploratory compounds, the histone deacetylase SAHA and the natural product andrographolide, on Uppsala 87 Malignant Glioma (U-87 MG) cell migration and viability in comparison with the clinically used therapeutic agent temozolomide (TMZ). We used the electric cell-substrate impedance sensing (ECIS) system to monitor the migration of U-87 MG cells after treatment with various concentrations of these compounds. Moreover, we used the Alamar blue assay and western blotting to observe the concentration-dependent changes in the viability and apoptosis of U-87 MG cells. Our results demonstrated that both SAHA and andrographolide (10-300 µM) significantly inhibited GBM cell migration in a concentration-dependent manner, and 10 µM SAHA and 56 µM andrographolide demonstrated remarkable inhibitory effects on U-87 MG migration. Western blotting indicated that compared with TMZ, both SAHA and andrographolide induced higher expression levels of apoptosis-related proteins, such as caspase-3, BAX, and PARP in U-87 MG cells. Furthermore, all three drugs downregulated the expression of the antiapoptotic protein Bcl-2. In conclusion, SAHA and andrographolide showed exceptional results in inhibiting cell migration and motility. The ECIS wound healing assay is a powerful technique to identify and screen potential therapeutic agents that can inhibit cancer cell migration.


Assuntos
Técnicas Biossensoriais , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Impedância Elétrica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Temozolomida/farmacologia , Vorinostat/farmacologia
8.
Chem Biol Interact ; 306: 54-61, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30958996

RESUMO

In the present study, we investigated the p53-independent mechanism by which quercetin (Q) increased apoptosis in human lung cancer H1299 cells exposed to trichostatin A (TSA), a histone deacetylase inhibitor. We also investigated the role of Q in increasing the acetylation of histones H3 and H4 and the possible mechanism. Q at 5 µM significantly increased apoptosis by 88% in H1299 cells induced by TSA at 72 h. Q also significantly increased TSA-induced death receptor 5 (DR5) mRNA and protein expression as well as caspase-10/3 activities in H1299 cells. Transfection of DR5 siRNA into H1299 cells significantly diminished the enhancing effects of Q on TSA-induced apoptosis. Furthermore, TSA in combination with Q rather than TSA alone significantly increased p300 expression. Transfection of p300 siRNA in H1299 cells significantly diminished the increase of histone H3/H4 acetylation, DR5 protein expression, caspase-10/3 activity and apoptosis induced by Q. In addition, similar effects of Q were observed when Q was combined with vorinostat, another FDA-approved histone deacetylase inhibitor. These data suggest that the up-regulation of p300 expression, which in turn increases histone acetylation and DR5 expression, plays an important role in the enhancing effect of Q on TSA/vorinostat- induced apoptosis in H1299 cells.


Assuntos
Antineoplásicos/farmacologia , Proteína p300 Associada a E1A/genética , Ácidos Hidroxâmicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Quercetina/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína p300 Associada a E1A/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Vorinostat/farmacologia
9.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-31014028

RESUMO

In early diabetes, hyperglycemia and the associated metabolic dysregulation promote early changes in the functional properties of cardiomyocytes, progressively leading to the appearance of the diabetic cardiomyopathy phenotype. Recently, the interplay between histone acetyltransferases (HAT) and histone deacetylases (HDAC) has emerged as a crucial factor in the development of cardiac disorders. The present study evaluates whether HDAC inhibition can prevent the development of cardiomyocyte contractile dysfunction induced by a short period of hyperglycemia, with focus on the potential underlying mechanisms. Cell contractility and calcium dynamics were measured in unloaded ventricular myocytes isolated from the heart of control and diabetic rats. Cardiomyocytes were either untreated or exposed to the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) for 90 min. Then, a fraction of each group of cells was used to evaluate the expression levels of proteins involved in the excitation-contraction coupling, and the cardiomyocyte metabolic activity, ATP content, and reactive oxygen species levels. SAHA treatment was able to counteract the initial functional derangement in cardiomyocytes by reducing cell oxidative damage. These findings suggest that early HDAC inhibition could be a promising adjuvant approach for preventing diabetes-induced cardiomyocyte oxidative damage, which triggers the pro-inflammatory signal cascade, mitochondrial damage, and ventricular dysfunction.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Vorinostat/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
10.
Mol Neurobiol ; 56(10): 6986-7002, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30963442

RESUMO

Multidrug resistance protein 1 (MDR1, ABCB1, P-glycoprotein) is a critical efflux transporter that extrudes chemicals from the blood-brain barrier (BBB) and limits neuronal exposure to xenobiotics. Prior studies in malignant cells demonstrated that MDR1 expression can be altered by inhibition of histone deacetylases (HDAC), enzymes that modify histone structure and influence transcription factor binding to DNA. Here, we sought to identify the mechanisms responsible for the up-regulation of MDR1 by HDAC inhibitors in human BBB cells. Immortalized human brain capillary endothelial (hCMEC/D3) cells were treated with HDAC inhibitors and assessed for MDR1 expression and function. Of the HDAC inhibitors profiled, valproic acid (VPA), apicidin, and suberoylanilide hydroxamic acid (SAHA) increased MDR1 mRNA and protein levels by 30-200%, which corresponded with reduced intracellular accumulation of the MDR1 substrate rhodamine 123. Interestingly, induction of MDR1 mRNA by HDAC inhibitors mirrored increases in the expression of the aryl hydrocarbon receptor (AHR) and its target gene cytochrome P450 1A1. To explore the role of AHR in HDAC inhibitor-mediated regulation of MDR1, a pharmacological activator (ß-naphthoflavone, ßNF) and inhibitor (CH-223191, CH) of AHR were tested. The induction of MDR1 in cells treated with SAHA was amplified by ßNF and attenuated by CH. Furthermore, SAHA increased the binding of acetylated histone H3K9/K14 and AHR proteins to regions of the MDR1 promoter that contain AHR response elements. In conclusion, HDAC inhibitors up-regulate the expression and activity of the MDR1 transporter in human brain endothelial cells by increasing histone acetylation and facilitating AHR binding at the MDR1 promoter.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Encéfalo/citologia , Células Endoteliais/metabolismo , Histonas/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Acetilação , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Células Endoteliais/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Modelos Biológicos , Regiões Promotoras Genéticas , Ligação Proteica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Vorinostat/farmacologia
11.
Biol Pharm Bull ; 42(3): 448-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828077

RESUMO

Combination therapy is often an effective strategy to treat cancer. In this study, we examined the growth-inhibitory effects of Am80 (tamibarotene), a specific retinoic acid receptor (RAR) α/ß agonist, in combination with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), or a DNA methyl transferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine, on androgen receptor (AR)-positive and AR-negative prostate cancer cell lines (LNCaP and PC-3, respectively). We found that the combination therapy of SAHA and Am80 showed an enhanced growth-inhibitory effect on LNCaP cells. Further studies with various HDAC isotype-selective inhibitors showed that SAHA and KD5170 (a selective class I and II HDAC inhibitor) each increased the RARα protein level in LNCaP cells. Our results indicate that the target of the enhancing effect belongs to the Class IIb HDACs, especially HDAC6. Dual targeting of Class IIb HDAC and RARα may be a candidate therapeutic strategy for prostate cancer.


Assuntos
Benzoatos/uso terapêutico , Decitabina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Piridinas/farmacologia , Sulfonamidas/farmacologia , Tetra-Hidronaftalenos/uso terapêutico , Vorinostat/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Linhagem Celular Tumoral , Decitabina/administração & dosagem , Sinergismo Farmacológico , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Piridinas/administração & dosagem , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Sulfonamidas/administração & dosagem , Tetra-Hidronaftalenos/administração & dosagem , Tetra-Hidronaftalenos/farmacocinética , Vorinostat/administração & dosagem
12.
Int J Med Sci ; 16(3): 424-442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911277

RESUMO

T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Linfoma de Células T/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia/fisiologia , Citocinas/metabolismo , Depsipeptídeos/administração & dosagem , Depsipeptídeos/farmacologia , Epigênese Genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Linfoma de Células T/enzimologia , Sulfonamidas/administração & dosagem , Vorinostat/farmacologia
13.
J Toxicol Sci ; 44(3): 177-189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30842370

RESUMO

Recent studies have shown that sevoflurane can cause long-term neurotoxicity and learning and memory impairment in developing and progressively neurodegenerative brains. Sevoflurane is a widely used volatile anesthetic in clinical practice. Late gestation is a rapidly developing period in the fetal brain, but whether sevoflurane anesthesia during late gestation affects learning and memory of offspring is not fully elucidated. Histone deacetylase 2 (HDAC2) plays an important regulatory role in learning and memory. This study examined the effect of maternal sevoflurane exposure on learning and memory in offspring and the underlying role of HDAC2. The Morris water maze (MWM) test was used to evaluate learning and memory function. Q-PCR and immunofluorescence staining were used to measure the expression levels of genes related to learning and memory. The results showed that sevoflurane anesthesia during late gestation impaired learning and memory in offspring rats (e.g., showing increase of the escape latency and decrease of the platform-crossing times and target quadrant traveling time in behavior tests) and upregulated the expression of HDAC2, while downregulating the expression of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the N-methyl-D-aspartate receptor 2 subunit B (NR2B) mRNA and protein in the hippocampus of offspring in a time-dependent manner. HDAC2 inhibitor suberoylanilide hydroxamic acid (SAHA) treatment alleviated all of these changes in offspring rats. Therefore, the present study indicates that sevoflurane exposure during late gestation impairs offspring rat's learning and memory via upregulation of the expression of HDAC2 and downregulation of the expression of CREB and NR2B. SAHA can alleviate these impairments.


Assuntos
Anestésicos Inalatórios/toxicidade , Inibidores de Histona Desacetilases/farmacologia , Aprendizagem/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Sevoflurano/toxicidade , Vorinostat/farmacologia , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/genética , Masculino , Troca Materno-Fetal , Gravidez , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética
14.
Differentiation ; 106: 1-8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818187

RESUMO

Adipogenesis is an important biological process that is linked to obesity and metabolic disorders. On the other hand, fat regeneration is crucial as a restorative approach following mastectomy or severe burn injury. Furthermore, optimizing an in-vitro model of adipogenesis, which would help in understanding the possible effects and/or side effects of fat-soluble drugs and anti-obesity remedies, in addition to the developmental studies. Epigenetic is an important factor that is involved in cellular differentiation and commitment. This study aimed at investigating the effect of DNA methylation and histone deactylases inhibitors, 5-Aza-deoxycytidine (5-Aza-dC) and Suberoylanilide hydroxamic acid (SAHA), on the adipogenic differentiation process. The two modifiers were applied according to our previously published protocol, followed by three cycles of a classical, two-step adipogenesis protocol. The cells pretreated with SAHA showed enhanced expression of the many adipogenic genes, including peroxisome proliferator-activated receptor-γ as well as the accumulation of intracytoplasmic fat as shown by oil red and Nile red staining and the secretion of adipokines, such as MCP-1 and IP-10. On contrary, 5-Aza-dC inhibited all these markers. In conclusion, adding the reported step with SAHA to the differentiation protocols could have an impact on the progress of the in-vitro fat regenerative approach. The possible role of 5-Aza-dC in the inhibition of adipogenesis can be of clinical interest and will need further characterization in the future.


Assuntos
Adipogenia/efeitos dos fármacos , Azacitidina/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Epigênese Genética , Osteossarcoma/tratamento farmacológico , Vorinostat/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Diferenciação Celular , Proliferação de Células , Metilação de DNA , Inibidores de Histona Desacetilases/farmacologia , Humanos , Osteossarcoma/genética , Osteossarcoma/patologia , Células Tumorais Cultivadas
15.
Biomater Sci ; 7(4): 1335-1344, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30816393

RESUMO

Cancer radiation therapy (RT) is limited by endogenous DNA repair of tumor cells and microenvironmental hypoxia in tumor tissues. Herein, we demonstrated an effective cancer chemo-radiotherapy strategy based on choline phosphate liposomal nanomedicines, which inhibit the intrinsic radioresistance of RT and concomitantly harness the RT-induced hypoxia to produce additional toxicity to overcome post-RT radioresistance. To achieve this strategy, a radiotherapy sensitizer, vorinostat, and a hypoxia-activated banoxantrone dihydrochloride (AQ4N) were simultaneously delivered to a tumor using liposomes composed of an inverted polarity lipid 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl ethyl phosphate (DOCPe). The DOCPe liposomes exhibited a longer blood circulation time and enhanced tumor accumulation, compared to their zwitterionic phosphocholine counterpart. The RT was sensitized by vorinostat to kill non-tolerant normoxic tumor cells efficiently. The irradiation aggravated hypoxia-activated AQ4N to further potentiate RT treatment. This chemo-radiotherapy combination showed excellent tumor treatment efficacy and is promising for future clinical translation.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Quimiorradioterapia , Neoplasias Mamárias Animais/terapia , Nanomedicina , Fosforilcolina/química , Vorinostat/farmacologia , Animais , Antraquinonas/química , Antineoplásicos/química , Hipóxia Celular/efeitos dos fármacos , Feminino , Lipossomos/sangue , Lipossomos/química , Lipossomos/farmacocinética , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Fosforilcolina/sangue , Fosforilcolina/farmacocinética , Vorinostat/química
16.
Oncol Rep ; 41(4): 2089-2102, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816528

RESUMO

Papillary renal cell carcinoma (PRCC) accounts for 15­20% of all kidney neoplasms and continually attracts attention due to the increase in the incidents in which it occurs. The molecular mechanism of PRCC remains unclear and the efficacy of drugs that treat PRCC lacks sufficient evidence in clinical trials. Therefore, it is necessary to investigate the underlying mechanism in the development of PRCC and identify additional potential anti­PRCC drugs for its treatment. The differently expressed genes (DEGs) of PRCC were identified, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses for functional annotation. Then, potential drugs for PRCC treatment were predicted by Connectivity Map (Cmap) based on DEGs. Furthermore, the latent function of query drugs in PRCC was explored by integrating drug­target, drug­pathway and drug­protein interactions. In total, 627 genes were screened as DEGs, and these DEGs were annotated using KEGG pathway analyses and were clearly associated with the complement and coagulation cascades, amongst others. Then, 60 candidate drugs, as predicted based on DEGs, were obtained from the Cmap database. Vorinostat was considered as the most promising drug for detailed discussion. Following protein­protein interaction (PPI) analysis and molecular docking, vorinostat was observed to interact with C3 and ANXN1 proteins, which are the upregulated hub genes and may serve as oncologic therapeutic targets in PRCC. Among the top 20 metabolic pathways, several significant pathways, such as complement and coagulation cascades and cell adhesion molecules, may greatly contribute to the development and progression of PRCC. Following the performance of the PPI network and molecular docking tests, vorinostat exhibited a considerable and promising application in PRCC treatment by targeting C3 and ANXN1.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Renais/genética , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/química , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Biologia Computacional , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular/métodos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Vorinostat/química , Vorinostat/farmacologia , Vorinostat/uso terapêutico
17.
Genome Biol ; 20(1): 49, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823893

RESUMO

Histone acetylation plays a central role in gene regulation and is sensitive to the levels of metabolic intermediates. However, predicting the impact of metabolic alterations on acetylation in pathological conditions is a significant challenge. Here, we present a genome-scale network model that predicts the impact of nutritional environment and genetic alterations on histone acetylation. It identifies cell types that are sensitive to histone deacetylase inhibitors based on their metabolic state, and we validate metabolites that alter drug sensitivity. Our model provides a mechanistic framework for predicting how metabolic perturbations contribute to epigenetic changes and sensitivity to deacetylase inhibitors.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Metabolismo , Modelos Genéticos , Vorinostat/farmacologia , Acetilação , Células HeLa , Humanos
18.
J Biol Chem ; 294(14): 5576-5589, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30745362

RESUMO

Histone deacetylase (HDAC) inhibitors (HDACis) have been widely tested in clinical trials for their ability to reverse HIV latency but have yielded only limited success. One HDACi, suberoylanilide hydroxamic acid (SAHA), exhibits off-target effects on host gene expression predicted to interfere with induction of HIV transcription. Romidepsin (RMD) has higher potency and specificity for class I HDACs implicated in maintaining HIV provirus in the latent state. More robust HIV reactivation has indeed been achieved with RMD use ex vivo than with SAHA; however, reduction of viral reservoir size has not been observed in clinical trials. Therefore, using RNA-Seq, we sought to compare the effects of SAHA and RMD on gene expression in primary CD4+ T cells. Among the genes whose expression was modulated by both HDACi agents, we identified genes previously implicated in HIV latency. Two genes, SMARCB1 and PARP1, whose modulation by SAHA and RMD is predicted to inhibit HIV reactivation, were evaluated in the major maturation subsets of CD4+ T cells and were consistently either up- or down-regulated by both HDACi compounds. Our results indicate that despite having different potencies and HDAC specificities, SAHA and RMD modulate an overlapping set of genes, implicated in HIV latency regulation. Some of these genes merit exploration as additional targets to improve the therapeutic outcomes of "shock and kill" strategies. The overall complexity of HDACi-induced responses among host genes with predicted stimulatory or inhibitory effects on HIV expression likely contributes to differential HDACi potencies and dictates the outcome of HIV reactivation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Depsipeptídeos/farmacologia , HIV-1/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Ativação Viral/efeitos dos fármacos , Vorinostat/farmacologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Poli(ADP-Ribose) Polimerase-1/biossíntese , Proteína SMARCB1/biossíntese , Transcrição Genética/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
19.
Biosci Rep ; 39(2)2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30745455

RESUMO

Missense mutations in the TP53 gene produce mutant p53 (mutp53) proteins which may acquire oncogenic properties favoring chemoresistance, cell migration, and metastasis. The exploitation of cellular pathways that promote mutp53 degradation may reduce cell proliferation and invasion as well as increase the sensitivity to anticancer drugs, with a strong impact on current cancer therapies. In the last years, several molecules have been characterized for their ability to induce the degradation of mutp53 through the activation of autophagy. Here, we investigated the correlation between autophagy and mutp53 degradation induced by suberoylanilide hydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor. In the human cancer lines MDA-MB-231 (mutp53-R280K) and DLD1 (mutp53-S241F), SAHA induced a significant mutp53 degradation. However, such degradation correlated with autophagy induction only in MDA-MB-231 cells, being counteracted by autophagy inhibition, which also increased SAHA-induced cell death. Conversely, in DLD1 cells SAHA triggered a low level of autophagy despite promoting a strong decrease in mutp53 level, and autophagy inhibition did not change either mutp53 levels or sensitivity to this drug. We conclude that autophagy can be a relevant pathway for mutp53 degradation induced by SAHA, but its contribution to mutp53 destabilization and the consequences on cell death are likely context-dependent.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Vorinostat/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Mutação , Proteólise/efeitos dos fármacos
20.
Medicina (Kaunas) ; 55(2)2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30700046

RESUMO

BACKGROUND AND OBJECTIVE: Alterations in gene expressions are often due to epigenetic modifications that can have a significant influence on cancer development, growth, and progression. Lately, histone deacetylase inhibitors (HDACi) such as suberoylanilide hydroxamic acid (SAHA, or vorinostat, MK0683) have been emerging as a new class of drugs with promising therapeutic benefits in controlling cancer growth and metastasis. The small molecule RG7388 (idasanutlin, R05503781) is a newly developed inhibitor that is specific for an oncogene-derived protein called MDM2, which is also in clinical trials for the treatment of various types of cancers. These two drugs have shown the ability to induce p21 expression through distinct mechanisms in MCF-7 and LNCaP cells, which are reported to have wild-type TP53. Our understanding of the molecular mechanism whereby SAHA and RG7388 can induce cell cycle arrest and trigger cell death is still evolving. In this study, we performed experiments to measure the cell cycle arrest effects of SAHA and RG7388 using MCF-7 and LNCaP cells. MATERIALS AND METHODS: The cytotoxicity, cell cycle arrest, and apoptosis/necroptosis effects of the SAHA and RG7388 treatments were assessed using the Trypan Blue dye exclusion (TBDE) method, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence assay with DEVD-amc substrate, and immunoblotting methods. RESULTS: The RG7388 treatment was able to induce cell death by elevating p21WAF1/CIP1 through inhibition of MDM2 in LNCaP, but not in MCF-7 cells, even though there was evidence of p53 elevation. Hence, we suspect that there is some level of uncoupling of p53-mediated transcriptional induction of p21WAF1/CIP1 in MCF-7 cells. CONCLUSION: Our results from MCF-7 and LNCaP cells confirmed that SAHA and RG7388 treatments were able to induce cell death via a combination of cell cycle arrest and cytotoxic mechanisms. We speculate that our findings could lead to the development of newer treatments for breast and prostate cancers with drug combinations including HDACi.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirrolidinas/farmacologia , Vorinostat/farmacologia , para-Aminobenzoatos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Células MCF-7 , Masculino , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/uso terapêutico , Proteína Supressora de Tumor p53/biossíntese , Vorinostat/uso terapêutico , para-Aminobenzoatos/uso terapêutico
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