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1.
Molecules ; 26(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34641289

RESUMO

The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.


Assuntos
Neoplasias da Mama/enzimologia , Inibidores de Histona Desacetilases/farmacologia , Cetonas/síntese química , Neuroblastoma/enzimologia , Vorinostat/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Cetonas/química , Cetonas/farmacologia , Células MCF-7 , Neuroblastoma/tratamento farmacológico
2.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638754

RESUMO

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment method of GBM. However, the intrinsic radioresistance of GBM cells is a key reason of poor therapeutic efficiency. Recently, many studies have shown that using the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy may improve the prognosis of GBM patients, but the underlying molecular mechanisms remain unclear. In this study, Gene Expression Omnibus (GEO) datasets GSE153982 and GSE131956 were analyzed to evaluate radiation-induced changes of gene expression in GBM without or with SAHA treatment, respectively. Additionally, the survival-associated genes of GBM patients were screened using the Chinese Glioma Genome Atlas (CGGA) database. Taking the intersection of these three datasets, 11 survival-associated genes were discovered to be activated by irradiation and regulated by SAHA. The expressions of these genes were further verified in human GBM cell lines U251, T98G, and U251 homologous radioresistant cells (U251R) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was found that MMP14 mRNA was considerably highly expressed in the radioresistant cell lines and was reduced by SAHA treatment. Transfection of MMP14 siRNA (siMMP14) suppressed cell survivals of these GBM cells after irradiation. Taken together, our results reveal for the first time that the MMP14 gene contributed to SAHA-induced radiosensitization of GBM.


Assuntos
Quimiorradioterapia , Bases de Dados de Ácidos Nucleicos , Glioblastoma , Inibidores de Histona Desacetilases/farmacologia , Metaloproteinase 14 da Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Vorinostat/farmacologia , Linhagem Celular Tumoral , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Metaloproteinase 14 da Matriz/genética , Proteínas de Neoplasias/genética , Vorinostat/farmacocinética
3.
J Biol Chem ; 297(3): 101070, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34389355

RESUMO

Transforming growth factor-beta 2 (TGF-ß2) is highly concentrated in the aqueous humor of primary open-angle glaucoma patients. TGF-ß2 causes fibrosis of outflow tissues, such as the trabecular meshwork (TM), and increases intraocular pressure by increasing resistance to aqueous humor outflow. Recently, histone deacetylase (HDAC) activity was investigated in fibrosis in various tissues, revealing that HDAC inhibitors suppress tissue fibrosis. However, the effect of HDAC inhibitors on fibrosis in the eye was not determined. Here, we investigated the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on TGF-ß2-induced increased resistance to aqueous humor outflow. We found that SAHA suppressed TGF-ß2-induced outflow resistance in perfused porcine eyes. Moreover, SAHA cotreatment suppressed TGF-ß2-induced ocular hypertension in rabbits. The permeability of monkey TM (MTM) and Schlemm's canal (MSC) cell monolayers was decreased by TGF-ß2 treatment. SAHA inhibited the effects of TGF-ß2 on the permeability of these cells. TGF-ß2 also increased the expression of extracellular matrix proteins (fibronectin and collagen type I or IV) in MTM, MSC, and human TM (HTM) cells, while SAHA inhibited TGF-ß2-induced extracellular matrix protein expression in these cells. SAHA also inhibited TGF-ß2-induced phosphorylation of Akt and ERK, but did not inhibit Smad2/3 phosphorylation, the canonical pathway of TGF-ß signaling. Moreover, SAHA induced the expression of phosphatase and tensin homolog, a PI3K/Akt signaling factor, as well as bone morphogenetic protein 7, an endogenous antagonist of TGF-ß. These results imply that SAHA prevents TGF-ß2-induced increases in outflow resistance and regulates the non-Smad pathway of TGF-ß signaling in TM and MSC cells.


Assuntos
Fator de Crescimento Transformador beta2/metabolismo , Vorinostat/metabolismo , Vorinostat/farmacologia , Animais , Humor Aquoso/metabolismo , Humor Aquoso/fisiologia , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Glaucoma de Ângulo Aberto/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Macaca fascicularis , Masculino , Hipertensão Ocular/metabolismo , Fosforilação , Cultura Primária de Células , Coelhos , Transdução de Sinais , Suínos , Malha Trabecular/efeitos dos fármacos , Fator de Crescimento Transformador beta2/fisiologia , Fatores de Crescimento Transformadores/metabolismo
4.
J Virol ; 95(19): e0022721, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34287050

RESUMO

Latent HIV reservoirs persist in people living with HIV despite effective antiretroviral therapy and contribute to rebound viremia upon treatment interruption. Macrophages are an important reservoir cell type, but analysis of agents that modulate latency in macrophages is limited by lack of appropriate in vitro models. We therefore generated an experimental system to investigate this by purifying nonproductively infected human monocyte-derived macrophages (MDM) following in vitro infection with an M-tropic enhanced green fluorescent protein reporter HIV clone and quantified activation of HIV transcription using live-cell fluorescence microscopy. The proportion of HIV-infected MDM was quantified by qPCR detection of HIV DNA, and GFP expression was validated as a marker of productive HIV infection by colabeling of HIV Gag protein. HIV transcription spontaneously reactivated in latently infected MDM at a rate of 0.22% ± 0.04% cells per day (mean ± the standard error of the mean, n = 10 independent donors), producing infectious virions able to infect heterologous T cells in coculture experiments, and both T cells and TZM-bl cells in a cell-free infection system using MDM culture supernatants. Polarization to an M1 phenotype with gamma interferon plus tumor necrosis factor resulted in a 2.3-fold decrease in initial HIV infection of MDM (P < 0.001, n = 8) and a 1.4-fold decrease in spontaneous reactivation (P = 0.025, n = 6), whereas M2 polarization using interleukin-4 prior to infection led to a 1.6-fold decrease in HIV infectivity (P = 0.028, n = 8) but a 2.0-fold increase in the rate of HIV reactivation in latently infected MDM (P = 0.023, n = 6). The latency reversing agents bryostatin and vorinostat, but not panobinostat, significantly induced HIV reactivation in latently infected MDM (P = 0.031 and P = 0.038, respectively, n = 6). IMPORTANCE Agents which modulate latent HIV reservoirs in infected cells are of considerable interest to HIV cure strategies. The present study characterizes a robust, reproducible model enabling quantification of HIV reactivation in primary HIV-infected human MDM which is relatively insensitive to the monocyte donor source and hence suitable for evaluating latency modifiers in MDM. The rate of initial viral infection was greater than the rate of HIV reactivation, suggesting that different mechanisms regulate these processes. HIV reactivation was sensitive to macrophage polarization, suggesting that cellular and tissue environments influence HIV reactivation in different macrophage populations. Importantly, latently infected MDM showed different susceptibilities to certain latency-reversing agents known to be effective in T cells, indicating that dedicated strategies may be required to target latently infected macrophage populations in vivo.


Assuntos
HIV-1/genética , HIV-1/fisiologia , Macrófagos/virologia , Transcrição Genética , Ativação Viral , Briostatinas/farmacologia , Citocinas/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Panobinostat/farmacologia , Linfócitos T/virologia , Latência Viral , Replicação Viral , Vorinostat/farmacologia
5.
J Biochem Mol Toxicol ; 35(9): e22844, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34250664

RESUMO

Osteoarthritis (OA) is a common joint disease that ultimately causes physical disability and imposes an economic burden on society. Cartilage destruction plays a key role in the development of OA. Vorinostat is an oral histone deacetylase (HDAC) inhibitor and has been used for the treatment of T-cell lymphoma. Previous studies have reported the anti-inflammatory effect of HDAC inhibitors in both in vivo and in vitro models. However, it is unknown whether vorinostat exerts a protective effect in OA. In this study, our results demonstrate that treatment with vorinostat prevents interleukin 1α (IL-1α)-induced reduction of type II collagen at both gene and protein levels. Treatment with vorinostat reduced the IL-1α-induced production of mitochondrial reactive oxygen species (ROS) in T/C-28a2 cells. Additionally, vorinostat rescued the IL-1α-induced decrease in the expression of the collagen type II a1 (Col2a1) gene and the expression of Sry-related HMG box 9 (SOX-9). Importantly, we found that vorinostat inhibited the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for the degradation of type II collagen. Furthermore, vorinostat suppressed the expression of E74-like factor 3 (ELF3), which is a key transcription factor that plays a pivotal role in the IL-1α-induced reduction of type II collagen. Also, the overexpression of ELF3 abolished the protective effects of vorinostat against IL-1α-induced loss of type 2 collagen by inhibiting the expression of SOX-9 whilst increasing the expression of MMP-13. In conclusion, our findings suggest that vorinostat might prevent cartilage destruction by rescuing the reduction of type II collagen, mediated by the suppression of ELF3.


Assuntos
Condrócitos/metabolismo , Colágeno Tipo II/biossíntese , Proteínas de Ligação a DNA/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1alfa/farmacologia , Proteínas Proto-Oncogênicas c-ets/biossíntese , Fatores de Transcrição/biossíntese , Vorinostat/farmacologia , Linhagem Celular , Humanos , Interleucina-1alfa/metabolismo
6.
EBioMedicine ; 69: 103457, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34224975

RESUMO

BACKGROUND: Histone acetylation/deacetylase process is one of the most studied epigenetic modifications. Histone deacetylase inhibitors (HDACis) have shown clinical benefits in haematological malignancies but failed in solid tumours due to the lack of biomarker-driven stratification. METHODS: We perform integrative pharmaco-transcriptomic analysis by correlating drug response profiles of five pan-HDACis with transcriptomes of solid cancer cell lines (n=659) to systematically identify generalizable gene signatures associated with HDACis sensitivity and resistance. The established signatures are then applied to identify cancer subtypes that are potentially sensitive or resistant to HDACis, and drugs that enhance the efficacy of HDACis. Finally, the reproductivity of the established HDACis signatures is evaluated by multiple independent drug response datasets and experimental assays. FINDINGS: We successfully delineate generalizable gene signatures predicting sensitivity (containing 46 genes) and resistance (containing 53 genes) to all five HDACis, with their reproductivity confirmed by multiple external sources and independent internal assays. Using the gene signatures, we identify low-grade glioma harbouring isocitrate dehydrogenase 1/2 (IDH1/2) mutation and non-YAP1-driven subsets of small-cell lung cancer (SCLC) that particularly benefit from HDACis monotherapy. Further, based on the resistance gene signature, we identify clinically-approved Dasatinib as a synthetic lethal drug with HDACi, synergizing in inducing apoptosis and reactive oxygen species on a panel of SCLC. Finally, Dasatinib significantly enhances the therapeutic efficacy of Vorinostat in SCLC xenografts. INTERPRETATION: Our work establishes robust gene signatures predicting HDACis sensitivity/resistance in solid cancer and uncovers combined Dasatinib/HDACi as a synthetic lethal combination therapy for SCLC. FUNDING: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias Pulmonares/genética , Transcriptoma , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Dasatinibe/administração & dosagem , Sinergismo Farmacológico , Humanos , Isocitrato Desidrogenase/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Variantes Farmacogenômicos , Fatores de Transcrição/genética , Vorinostat/administração & dosagem , Vorinostat/uso terapêutico
7.
Neurochem Res ; 46(9): 2285-2296, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34081246

RESUMO

It has been demonstrated that peripheral inflammation induces cognitive dysfunction. Several histone deacetylase (HDAC) inhibitors ameliorate cognitive dysfunction in animal models of not only peripheral inflammation but also Alzheimer's disease. However, it is not clear which HDAC expressed in the central nervous system or peripheral tissues is involved in the therapeutic effect of HDAC inhibition on cognitive dysfunction. Hence, the present study investigated the effect of peripheral HDAC inhibition on peripheral inflammation-induced cognitive dysfunction. Suberoylanilide hydroxamic acid (SAHA), a pan-HDAC inhibitor that is mainly distributed in peripheral tissues after intraperitoneal administration, was found to prevent peripheral inflammation-induced cognitive dysfunction. Moreover, pretreatment with SAHA dramatically increased mRNA expression of interleukin-10, an anti-inflammatory cytokine, in peripheral and central tissues and attenuated peripheral inflammation-induced microglial activation in the CA3 region of the hippocampus. Minocycline, a macrophage/microglia inhibitor, also ameliorated cognitive dysfunction. Furthermore, as a result of treatment with liposomal clodronate, depletion of peripheral macrophages partially ameliorated the peripheral inflammation-evoked cognitive dysfunction. Taken together, these findings demonstrate that inhibition of peripheral HDAC plays a critical role in preventing cognitive dysfunction induced by peripheral inflammation via the regulation of anti-inflammatory cytokine production and the inhibition of microglial functions in the hippocampus. Thus, these findings could provide support for inhibition of peripheral HDAC as a novel therapeutic strategy for inflammation-induced cognitive dysfunction.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Microglia/efeitos dos fármacos , Vorinostat/uso terapêutico , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Microglia/metabolismo
8.
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
9.
Drug Deliv ; 28(1): 963-972, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34036867

RESUMO

PD-1/PD-L1 blocking therapy has become one of the most promising methods in the field of tumor treatment. However, it encounters the challenge of immune escape due to the exhaustion of T cells. Studies have shown that the epigenetic regulation drug histone deacetylase inhibitor (HDACi) may be able to reverse exhausted T cells by changing the epigenetic transcription program. Therefore, the combination of epigenetic therapy and PD-1/PD-L1 blockade therapy is expected to reverse the immune escape, whereas the overriding goal should aim at the spontaneous release and synergy of PD-1/PD-L1 blocking siRNA and HDACi. In this study, we develop PDDS{polyethylene glycol-b-asparaginate(diethylenetriamine-vorinostat), (PEG-b-P[Asp(DET-SAHA)n] PPDS)}encapsulating siRNA-PD-L1to provide micelles siRNA-PD-L1-loaded micelles (siRNA@PPDS). Transmission electron microscope (TEM) images demonstrate that siRNA@PPDS micelles presented spherical morphology with a size of about 120 nm; hydrodynamic data analysis indicates pH sensitivity of siRNA@PPDS micelles. The experiments reveal that siRNA@PPDS micelles could be well uptaken by the tumor cells to silence the expression of PD-L1 protein in a dose-dependent manner; compared with the free SAHA, the SAHA-loaded micelles PPDS show higher cytotoxicity to induce tumor cell apoptosis and block cell cycle in G1 phase on melanoma-bearing mice, siRNA@PPDS has shown outstanding inhibition of tumor growth and pulmonary metastasis. By comprehensively activating the immune system, lysosome activable polymeric vorinostat encapsulating PD-L1KD for the combination therapy of PD-L1-KD and HDACIs can be an effective strategy to reverse the unresponsiveness of immune checkpoint inhibitors and a promising treatment to inhibit tumor growth, recurrence, and metastasis in clinic.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Micelas , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Vorinostat/farmacologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular , Química Farmacêutica , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Epigênese Genética , Fase G1/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Concentração de Íons de Hidrogênio , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Polietilenoglicóis/química , RNA Interferente Pequeno/administração & dosagem , Vorinostat/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cell Death Dis ; 12(6): 532, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031358

RESUMO

Human intestinal peptide transporter PEPT1 is commonly repressed in human colorectal cancer (CRC), yet its relationship with sensitivity to the common CRC treatment ubenimex has not previously been elucidated. In this study, we confirmed PEPT1 suppression in CRC using real-time quantitative polymerase chain reaction and western blotting and then investigated the underlying epigenetic pathways involved using bisulfite sequencing, chromatin immunoprecipitation, siRNA knockdown, and reporter gene assays. We found that PEPT1 transcriptional repression was due to both DNMT1-mediated DNA methylation of the proximal promoter region and HDAC1-mediated histone deacetylation, which blocked P300-mediated H3K18/27Ac at the PEPT1 distal promoter. Finally, the effects of the epigenetic activation of PEPT1 on the CRC response to ubenimex were evaluated using sequential combination therapy of decitabine and ubenimex both in vitro and in xenografts. In conclusion, epigenetic silencing of PEPT1 due to increased DNMT1 and HDAC1 expression plays a vital role in the poor response of CRC to ubenimex.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Transportador 1 de Peptídeos/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metilação de DNA/efeitos dos fármacos , Sinergismo Farmacológico , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Leucina/administração & dosagem , Leucina/análogos & derivados , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transportador 1 de Peptídeos/metabolismo , Vorinostat/administração & dosagem , Vorinostat/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Org Chem ; 86(11): 7773-7780, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34000192

RESUMO

Chalaniline B [1-anilino-2,8-dihydroxy-3-(hydroxymethyl)xanthone], an antibiotic previously isolated from vorinostat-treated Chalara sp., was prepared in 7 steps from 2-hydroxyxanthone by a route incorporating regioselective oxidative transformations (bromination at C1/C3, ketone directed Pd(II)-catalyzed hydroxylation at C8), installation of the C1-anilino moiety by a regioselective Buchwald-Hartwig amination reaction from 1,3-dibromo-2,8-dimethoxyxanthone, and late-stage hydroxymethylation at C3 using a Stille cross-coupling. Biological evaluation of deshydroxymethylchalaniline B (1-anilino-2,8-dihydroxyxanthone) revealed MIC values of 8 µg mL-1 (25 µM) against both methicillin resistant S. aureus and B. subtilis.


Assuntos
Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Compostos de Anilina , Antibacterianos/farmacologia , Fungos , Compostos Heterocíclicos com 3 Anéis , Vorinostat
13.
Biol Chem ; 402(4): 501-512, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33938179

RESUMO

Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a negative prognostic indicator. In these studies, we set out to investigate potential therapeutic strategies to counter the tumor-permissive properties of NO. We found that exposure to NO increased proliferation of TNBC cells and that treatment with the histone deacetylase inhibitor Vorinostat (SAHA) prevented this proliferation. When histone acetylation was measured in response to NO and/or SAHA, NO significantly decreased acetylation on histone 3 lysine 9 (H3K9ac) and SAHA increased H3K9ac. If NO and SAHA were sequentially administered to cells (in either order), an increase in acetylation was observed in all cases. Mechanistic studies suggest that the "deacetylase" activity of NO does not involve S-nitrosothiols or soluble guanylyl cyclase activation. The observed decrease in histone acetylation by NO required the interaction of NO with cellular iron pools and may be an overriding effect of NO-mediated increases in histone methylation at the same lysine residues. Our data revealed a novel pathway interaction of Vorinostat and provides new insight in therapeutic strategy for aggressive TNBCs.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Óxido Nítrico/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vorinostat/farmacologia , Acetilação/efeitos dos fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Vorinostat/química
14.
J Med Chem ; 64(11): 7468-7482, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34043359

RESUMO

Nowadays, simultaneous inhibition of multiple targets through drug combination is an important anticancer strategy owing to the complex mechanism behind tumorigenesis. Recent studies have demonstrated that the inhibition of histone deacetylases (HDACs) will lead to compensated activation of a notorious cancer-related drug target, signal transducer and activator of transcription 3 (STAT3), in breast cancer through a cascade, which probably limits the anti-proliferation effect of HDAC inhibitors in solid tumors. By incorporating the pharmacophore of the HDAC inhibitor SAHA (vorinostat) into the STAT3 inhibitor pterostilbene, a series of potent pterostilbene hydroxamic acid derivatives with dual-target inhibition activity were synthesized. An excellent hydroxamate derivate, compound 14, inhibited STAT3 (KD = 33 nM) and HDAC (IC50 = 23.15 nM) with robust potency in vitro. Compound 14 also showed potent anti-proliferation ability in vivo and in vitro. Our study provides the first STAT3 and HDAC dual-target inhibitor for further exploration.


Assuntos
Antineoplásicos/química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Meia-Vida , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/antagonistas & inibidores , Estilbenos/química , Estilbenos/metabolismo , Relação Estrutura-Atividade , Vorinostat/química , Vorinostat/metabolismo
15.
Pol J Vet Sci ; 24(1): 35-41, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33847090

RESUMO

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor (HDACi) that suppresses the growth of tumor cells in humans and canines. SAHA reportedly enhances the antitumor activity of human peripheral blood mononuclear cell (PBMC). However, it is unclear whether a similar effect is exerted in canines. The present study focused on the effect of SAHA on the cytotoxicity of IL-2 activated PBMC in three tumor cell lines (CTAC, CIPm, and MCM-N1). The mRNA expression of a ligand for the NKG2D receptor was upregulated in SAHA-treated cell lines. Moreover, the SAHA-treated cell lines, except MCM-N1 demonstrated a significantly higher PBMC cytotoxicity compared to the untreated cell lines. Therefore, the NKG2DL upregulation likely enhanced the interaction of NKG2D-NKG2DL, leading to enhanced cytotoxicity of PBMC. It was also revealed that activated PBMC treated with SAHA significantly attenuated their cytotoxicity toward all the cell lines. Although the NKG2D, NKp46, NKp44, and NKp30 receptors, involved in PBMC cytotoxicity, were presumed to be downregulated, there was no significant reduction in the mRNA expression of these receptors. This study revealed that SAHA not only sensitizes the canine tumor cells to cytotoxicity due to PBMC activation, but also suppresses the cytotoxicity of PBMC themselves. Therefore, our results highlight the necessity of avoiding this inhibitory action to enhance the antitumor effect of SAHA in canines.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Vorinostat/farmacologia , Animais , Linhagem Celular Tumoral , Doenças do Cão/tratamento farmacológico , Cães , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
Mol Vis ; 27: 151-160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33907370

RESUMO

PURPOSE: Recent reports linking HDAC6 to mitochondrial turnover and neurodegeneration led us to hypothesize that an inhibitor such as Vorinostat (suberoylanilide hydroxamic acid, SAHA) may reduce mitochondrial damage found in retinitis pigmentosa (RP), a progressive neurodegenerative disease of the eye. Here we tested the efficacy of SAHA for its ability to protect photoreceptors in in-vitro and in-situ models of RP. As the stressor, we focused on calcium overload. Calcium is one of the main drivers of cell death, and is associated with rod loss in the rd1 mouse retina, which harbors a mutation in the Pde6b gene similar to that found in human patients suffering from autosomal recessive RP. METHOD: Murine photoreceptor cell line (661W) were exposed to agents that led to calcium stress. Cell survival and redox capacity were measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, real-time changes in cellular metabolism were assessed using the Seahorse Biosciences XF24 analyzer, and mitochondrial fission-fusion using imaging. In-situ, neuroprotection was assessed in RPE/retina organ cultures of the rd1 mouse. SAHA effects on cell survival were compared in 661W cells with those of the specific HDAC6 inhibitor tubastatin A, and those on protein acetylation by Western blotting. RESULTS: In stressed 661W cells, SAHA was found to increase cell survival that was associated with improved mitochondrial respiration and reduced mitochondrial fission. The protective effects of SAHA were also observed on photoreceptor cell survival in whole retinal organ explants of the rd1 mouse. Even though tubastatin A was ineffective in increasing cell survival in 661W cells, HDAC6 activity was confirmed in 661W cells after SAHA treatment with protein acetylation specific for HDAC6, defined by an increase in tubulin, but not histone acetylation. CONCLUSIONS: SAHA was found to protect mitochondria from damage, and concomitantly reduced photoreceptor cell death in cell and organ cultures. The lack of activity of tubastatin A suggests that there must be an additional mechanism of action involved in the protective mechanism of SAHA that is responsible for its neuroprotection. Overall, SAHA may be a useful treatment for the prevention of photoreceptor degeneration associated with human RP. The results are discussed in the context of the effects of inhibitors that target different classes and members of the HDAC family and their effects on rod versus cone survival.


Assuntos
Modelos Animais de Doenças , Inibidores de Histona Desacetilases/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Retinite Pigmentosa/tratamento farmacológico , Vorinostat/uso terapêutico , Animais , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/prevenção & controle , NADH NADPH Oxirredutases/metabolismo , Técnicas de Cultura de Órgãos , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia
17.
Mol Imaging ; 2021: 6660358, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33867871

RESUMO

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Fluordesoxiglucose F18 , Humanos , Ácidos Hidroxâmicos , Pulmão , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Vorinostat/farmacologia
18.
Cells ; 10(5)2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33923163

RESUMO

Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity (Transcription factor EB-TFEB, forkhead boxO-FOXO) and autophagic flux in neuroblastoma cells. In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.


Assuntos
Autofagia , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Neuroblastoma/patologia , Animais , Antimaláricos/farmacologia , Cloroquina/farmacologia , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O3/genética , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Células Tumorais Cultivadas , Vorinostat/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
19.
J Endocrinol ; 249(3): 177-193, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33856361

RESUMO

Several histone deacetylase (HDAC) inhibitors have been shown to play beneficial roles in treating obesity and its related metabolic syndromes. However, the underlying mechanisms are still not understood well. In this study, we examined the potential roles of SAHA, a potent inhibitor of HDACs, on energy expenditure and explored the molecular mechanism involved. Our data showed that SAHA induces less lipid accumulation and smaller lipid droplets in cultured adipocytes. In vivo studies showing SAHA reduces body weight gain and increases core temperature in lean and obese mice. Furthermore, SAHA accelerates blood glucose disposal, improves insulin sensitivity and attenuates fatty liver in obese animals. Transcriptome sequencing found that a group of zinc finger proteins (Zfps) was up-regulated by SAHA. Functional studies showed that the knockdown of Zfp691 or Zfp719 largely abolishes SAHA-induced Ucp1 expression in adipocytes. ChIP assay showed that SAHA stimulates histone H3 acetylation at Zfp719 promoter. Luciferase reporter analysis revealed that Zfp719 activates Ucp1 promoter. As a consequence, forced expression of Zfp719 increases Ucp1 expression and promotes lipid catabolism in adipocytes. Taken together, our data indicate that by stimulating axis of ZFPs-UCP1, SAHA induces white fat browning and energy consumption, which makes it a potential drug for treating obesity and related metabolic dysfunctions.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos/fisiologia , Tecido Adiposo Branco , Proteínas de Ligação a DNA/metabolismo , Vorinostat/farmacologia , Animais , Glicemia , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Camundongos , Dedos de Zinco
20.
Biochem Pharmacol ; 188: 114546, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33838133

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The failure of chemotherapy in HCC patients is partly due to inadequate intracellular drug accumulation caused by abnormally expressed drug transporters. Human organic anion transporter 2 (hOAT2), a transporter mainly expressed in liver and kidney, is responsible for uptake of various antineoplastic drugs such as 5-fluorouracil (5-FU). Among 32 pairs of human HCC samples, we preliminarily found that OAT2 was suppressed in HCC tissues compared with matched tumor-adjacent tissues at both mRNA and protein levels, which resulted in 5-FU resistance in HCC. However, the epigenetic regulatory mechanisms of OAT2 downregulation have not been investigated. In this study, we first proved it was histone hypoacetylation rather than DNA hypermethylation that participated in transcriptional repression of OAT2 in two HCC cell lines (BEL-7402 and SMMC-7721). In general, there were two pathways confirmed using tissues and cells: 1) Increased histone deacetylase sirtuin 7 (SIRT7) mediated loss of histone 3 lysine 18 acetylation (H3K18ac) at the promoter of OAT2 and inhibited its transcription. 2) More histone deacetylase 7 (HDAC7) instead of lysine acetyltransferase 8 (KAT8) enrichment at the promoter of OAT2 led to low levels of histone 4 lysine 16 acetylation (H4K16ac). Further, we found that histone deacetylases inhibitor vorinostat (SAHA) could reverse histone hypoacetylation state to activate OAT2 transcription and enhance uptake of classic OAT2 substrate zidovudine. Therefore, we evaluated the effect of combining SAHA and 5-FU and the results demonstrated that SAHA could sensitize HCC cells to 5-FU. Collectively, we proposed such a combination treatment to overcome 5-FU resistance in HCC from the perspective of epigenetically restoring OAT2.


Assuntos
Carcinoma Hepatocelular/metabolismo , Fluoruracila/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/biossíntese , Neoplasias Hepáticas/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Acetilação/efeitos dos fármacos , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Relação Dose-Resposta a Droga , Fluoruracila/uso terapêutico , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Histona Desacetilases/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Vorinostat/farmacologia
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