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1.
Anticancer Res ; 40(7): 3669-3683, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32620606

RESUMO

BACKGROUND/AIM: Triple negative cancer (TNBC) is a subtype of breast cancer that is highly aggressive, with poor prognosis and responds differently to treatments. This study investigated the role of vorinostat and indole-3-carbinol (I3C) on regulating critical receptors that are not normally expressed in TNBC. MATERIALS AND METHODS: Using real-time PCR, immunostaining, and western blots, the re-expression of estrogen receptor α (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) receptors was examined in four different TNBC cell types. RESULTS: ERα was re-expressed in three subtypes using vorinostat and I3C. Re-expression of the PR by vorinostat was also detected. Neither vorinostat nor I3C resulted in re-expression of the HER2 receptor. A significant decrease in growth and sensitivity to tamoxifen was also noted. CONCLUSION: The results of this study show that vorinostat and I3C modulate the re-expression of critical receptors in certain subtypes of TNBC through several pathways and these effects can be influenced by the molecular profiles of TNBCs.


Assuntos
Antineoplásicos/farmacologia , Receptor alfa de Estrogênio/metabolismo , Indóis/farmacologia , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Vorinostat/farmacologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Receptor ErbB-2/metabolismo
2.
Am J Pathol ; 190(10): 2155-2164, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32679231

RESUMO

Aberrant DNA methylation is an epigenetic hallmark of melanoma, but the expression of DNA methyltransferase (Dnmt)-1 in melanocytic tumors is unknown. Dnmt1 expression was analyzed in primary melanocytes, melanoma cell lines, and 83 melanocytic tumors, and its associations with proliferation, mutational status, and response to B-Raf and mitogen-activated protein kinase kinase (MEK) inhibition were explored. Dnmt1 expression was increased incrementally from nevi [mean fluorescence intensity (MFI), 48.1; interquartile range, 41.7 to 59.6] to primary melanomas (MFI, 68.8; interquartile range, 58.4 to 77.0) and metastatic melanomas (MFI, 87.5; interquartile range, 77.1 to 114.5) (P < 0.001). Dnmt1 expression was correlated with Ki-67 expression (Spearman correlation, 0.483; P < 0.001) and was independent of BRAF mutation status (P = 0.55). In BRAF-mutant melanoma, Dnmt1 was down-regulated during response to B-Raf and MEK inhibition and was again up-regulated on drug resistance in vitro and in vivo. Degradation of Dnmt1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid was associated with decreased cell viability in B-Raf inhibitor-sensitive and -resistant cell lines. This study demonstrates that Dnmt1 expression is correlated with proliferation in melanocytic tumors, is increased with melanoma progression, and is associated with response to B-Raf and MEK inhibition. Given its strong expression in metastatic melanoma, Dnmt1 may be a promising target for combined epigenetic and immunotherapy.


Assuntos
Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Melanoma/metabolismo , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/metabolismo , Linhagem Celular Tumoral , DNA/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanoma/genética , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Vorinostat/farmacologia
3.
Int J Nanomedicine ; 15: 4063-4078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606664

RESUMO

Background: Among various theories for the origin of cancer, the "stemness phenotype model" suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-ßcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-ßcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs. Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-ßcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay. Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction. Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.


Assuntos
Neoplasias da Mama/patologia , Carcinogênese/patologia , Ouro/química , Nanopartículas Metálicas/química , Células-Tronco Neoplásicas/patologia , Coroa de Proteína/química , Vorinostat/farmacologia , Proteínas Wnt/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Células MCF-7 , Nanosferas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Espectrofotometria Ultravioleta , Proteínas Wnt/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
4.
Biomed Res Int ; 2020: 1357630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190647

RESUMO

Identifying the potential side effects of drugs is crucial in clinical trials in the pharmaceutical industry. The existing side effect prediction methods mainly focus on the chemical and biological properties of drugs. This study proposes a method that uses diverse information such as drug-drug interactions from DrugBank, drug-drug interactions from network, single nucleotide polymorphisms, and side effect anatomical hierarchy as well as chemical structures, indications, and targets. The proposed method is based on the assumption that properties used in drug repositioning studies could be utilized to predict side effects because the phenotypic expression of a side effect is similar to that of the disease. The prediction results using the proposed method showed a 3.5% improvement in the area under the curve (AUC) over that obtained when only chemical, indication, and target features were used. The random forest model delivered outstanding results for all combinations of feature types. Finally, after identifying candidate side effects of drugs using the proposed method, the following four popular drugs were discussed: (1) dasatinib, (2) sitagliptin, (3) vorinostat, and (4) clonidine.


Assuntos
Clonidina/farmacologia , Dasatinibe/farmacocinética , Aprendizado de Máquina , Fosfato de Sitagliptina/farmacologia , Vorinostat/farmacologia , Área Sob a Curva , Interações Medicamentosas , Reposicionamento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Polimorfismo de Nucleotídeo Único/genética
5.
Sci Rep ; 10(1): 3080, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080210

RESUMO

We performed two phase I trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1-2.3] vs. 3.5 months [95% CI, 1.7-5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8-9.8] vs. 12.7 months [95% CI, 7.1-18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Compostos de Boro/uso terapêutico , Glicina/análogos & derivados , Mutação/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Proteína Supressora de Tumor p53/genética , Vorinostat/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacologia , Compostos de Boro/efeitos adversos , Compostos de Boro/farmacologia , Glicina/efeitos adversos , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Resultado do Tratamento , Vorinostat/efeitos adversos , Vorinostat/farmacologia , Adulto Jovem
6.
J Antibiot (Tokyo) ; 73(6): 410-413, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32060485

RESUMO

The effects of epigenetic modulation on secondary metabolite biosynthesis were investigated with five Aspergillus species cultured in the presence of either the DNA methyltransferase inhibitor 5-azacitidine or the histone deacetylase inhibitor vorinostat. With Aspergillus calidoustus and Aspergillus westerdijkiae, fermentation in the presence of vorinostat (100 µM) induced significant changes in secondary metabolite profile with examples of both induction and repression. We identified putative biosynthetic gene clusters for emericellamide in A. calidoustus and ochratoxin in A. westerdijkiae. A substantial induction in production levels was observed for two secondary metabolites: the diketopiperazine alkaloid phenylahistin in A. calidoustus and the polyketide penicillic acid in A. westerdijkiae, indicating the potential of epigenetic regulation for the activation of silent fungal biosynthetic pathways.


Assuntos
Aspergillus/metabolismo , Azacitidina/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Vorinostat/farmacologia , Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Família Multigênica , Metabolismo Secundário/genética
7.
Cell Mol Life Sci ; 77(23): 5017-5030, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31955243

RESUMO

Ulcerative colitis (UC) is characterized by relapsing-remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and anti-inflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNFα or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3-/-). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3-/-. In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.


Assuntos
Epigênese Genética , Histonas/metabolismo , Doenças Inflamatórias Intestinais/genética , Interleucinas/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Receptores de Citocinas/metabolismo , Animais , Complexo CD3/metabolismo , Caspase 3/metabolismo , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Inflamação/patologia , Interleucina-12/metabolismo , Interleucinas/genética , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/genética , Fenótipo , Ligação Proteica/efeitos dos fármacos , Receptores de Citocinas/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Vorinostat/farmacologia
8.
J Immunother Cancer ; 8(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31940587

RESUMO

BACKGROUND: The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized. METHODS: We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach. RESULTS: VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the "do not eat me" signal CD47 on tumor cells. CONCLUSIONS: HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Trastuzumab/farmacologia , Ácido Valproico/farmacologia , Vorinostat/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/farmacologia , Humanos , Fagocitose/efeitos dos fármacos , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Receptores de IgG/metabolismo , Trastuzumab/administração & dosagem , Ácido Valproico/administração & dosagem , Vorinostat/administração & dosagem
9.
Exp Parasitol ; 210: 107831, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926147

RESUMO

Babesia (B.) bovis is one of the main etiological agents of bovine babesiosis, causes serious economic losses to the cattle industry. Control of bovine babesiosis has been hindered by the limited treatment selection for B. bovis, thus, new options are urgently needed. We explored the drug library and unbiasedly screened 640 food and drug administration (FDA) approved drug compounds for their inhibitory activities against B. bovis in vitro. The initial screening identified 13 potentially effective compounds. Four potent compounds, namely mycophenolic acid (MPA), pentamidine (PTD), doxorubicin hydrochloride (DBH) and vorinostat (SAHA) exhibited the lowest IC50 and then selected for further evaluation of their in vitro efficacies using viability, combination inhibitory and cytotoxicity assays. The half-maximal inhibitory concentration (IC50) values of MPA, PTD, DBH, SAHA were 11.38 ± 1.66, 13.12 ± 4.29, 1.79 ± 0.15 and 45.18 ± 7.37 µM, respectively. Of note, DBH exhibited IC50 lower than that calculated for the commonly used antibabesial drug, diminazene aceturate (DA). The viability result revealed the ability of MPA, PTD, DBH, SAHA to prevent the regrowth of treated parasite at 4 × and 2 × of IC50. Antagonistic interactions against B. bovis were observed after treatment with either MPA, PTD, DBH or SAHA in combination with DA. Our findings indicate the richness of FDA approved compounds by novel potent antibabesial candidates and the identified potent compounds especially DBH might be used for the treatment of animal babesiosis caused by B. bovis.


Assuntos
Antiprotozoários/farmacologia , Babesia bovis/efeitos dos fármacos , Animais , Antiprotozoários/toxicidade , Babesia bovis/crescimento & desenvolvimento , Babesiose/tratamento farmacológico , Babesiose/parasitologia , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , Cães , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Aprovação de Drogas , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/toxicidade , Pentamidina/farmacologia , Pentamidina/toxicidade , Bibliotecas de Moléculas Pequenas , Espectrometria de Fluorescência , Vorinostat/farmacologia , Vorinostat/toxicidade
10.
Exp Parasitol ; 210: 107833, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31935358

RESUMO

Safety precautions prior to contact lens usage is essential for preventing Acanthamoeba keratitis. Contact lens disinfecting solutions containing 3% hydrogen peroxide (H2O2) are known to exert amoebicidal effect against Acanthamoeba. Yet, these solutions need to be neutralized to prevent ocular irritation, which consequently may result in incomplete disinfection. In this study, amoebicidal effect of tert-butyl hydroperoxide (tBHP) was investigated and its efficacy was compared to those of hydrogen peroxide (H2O2). H2O2 and tBHP showed dose dependent amoebicidal effect, however high concentration of these compounds demonstrated cytotoxicity in human corneal epithelial (HCE) cells. To reduce their cytotoxicity, the concentrations of both compounds were diluted to 50 µM and subsequently combined with 10 µM vorinostat to enhance amoebicidal effect. Addition of vorinostat induced high amoebicidal effect against Acanthamoeba trophozoites, even at low concentrations of H2O2 or tBHP. Cellular damage induced by combined treatment of H2O2 or tBHP with vorinostat in Acanthamoeba were determined by assessing cell cycle arrest and apoptosis via FACS analysis. While 50 µM H2O2 combined with 10 µM vorinostat showed 36.26% cytotoxicity on HCE cells during 24 h exposure, 50 µM tBHP with 10 µM vorinostat did not show cytotoxicity on HCE cells. These findings suggest that the application of tBHP and vorinostat for Acanthamoeba keratitis treatment and contact lens disinfection system is highly plausible.


Assuntos
Acanthamoeba/efeitos dos fármacos , Antiprotozoários/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Vorinostat/farmacologia , terc-Butil Hidroperóxido/farmacologia , Acanthamoeba/citologia , Acanthamoeba/genética , Anti-Infecciosos Locais/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Córnea/citologia , Córnea/efeitos dos fármacos , Córnea/parasitologia , DNA de Protozoário/efeitos dos fármacos , DNA de Protozoário/fisiologia , Combinação de Medicamentos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/parasitologia , Humanos , Peróxido de Hidrogênio/farmacologia
11.
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
12.
Eur J Med Genet ; 63(2): 103661, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31051269

RESUMO

CHARGE syndrome is an autosomal dominant congenital disorder caused primarily by mutations in the CHD7 gene. Using a small molecule screen in a zebrafish model of CHARGE syndrome, we identified 4 compounds that rescue embryos from disease-like phenotypes. Our screen yielded DAPT, a Notch signaling inhibitor that could ameliorate the craniofacial, cranial neuronal and myelination defects in chd7 morphant zebrafish embryos. We discovered that Procainamide, an inhibitor of DNA methyltransferase 1, was able to recover the pattern of expression of isl2a, a cranial neuronal marker while also reducing the effect on craniofacial cartilage and myelination. M344, an inhibitor of Histone deacetylases had a strong recovery effect on craniofacial cartilage defects and could also modestly revert the myelination defects in zebrafish embryos. CHIC-35, a SIRT1 inhibitor partially restored the expression of isl2a in cranial neurons while causing a partial reversion of myelination and craniofacial cartilage defects. Our results suggest that a modular approach to phenotypic rescue in multi-organ syndromes might be a more successful approach to treat these disorders. Our findings also open up the possibility of using these compounds for other disorders with shared phenotypes.


Assuntos
Síndrome CHARGE/tratamento farmacológico , Síndrome CHARGE/fisiopatologia , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Dipeptídeos/farmacologia , Procainamida/farmacologia , Vorinostat/farmacologia , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/embriologia , Animais , Animais Geneticamente Modificados , Síndrome CHARGE/genética , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dipeptídeos/uso terapêutico , Modelos Animais de Doenças , Embrião não Mamífero/diagnóstico por imagem , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Embrião não Mamífero/fisiopatologia , Técnicas de Silenciamento de Genes , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Procainamida/uso terapêutico , Receptores Notch/antagonistas & inibidores , Sirtuína 1/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vorinostat/uso terapêutico , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
13.
Cornea ; 39(2): 245-249, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31724982

RESUMO

PURPOSE: The aim of this study was to reduce the cytotoxicity and improve the amoebicidal effect of polyhexamethylene biguanide (PHMB) at low concentrations by combining it with histone deacetylase (HDAC) inhibitors. METHODS: To reduce the cytotoxic effect on human corneal epithelial (HCE) cells, the concentration of PHMB was reduced to 0.0002%. To enhance the amoebicidal effect of PHMB, HDAC inhibitors such as suberoylanilide hydroxamic acid, MS275, or MC1568 were combined with it. Acanthamoeba and HCE cells were treated with 3 combinations to evaluate the amoebicidal and cytotoxic effects. Microscopy and fluorescence-activated cell sorting analysis were performed to investigate the apoptotic cell death of Acanthamoeba by these combinatorial treatments. RESULTS: The low concentration of PHMB (0.0002%) alone demonstrated no cytopathic effects (CPEs) on HCE cells. Three combinatorial treatments using 0.0002% PHMB with 10 µM suberoylanilide hydroxamic acid, 10 µM MS275, or 10 µM MC1568 showed higher amoebicidal effects on A. castellanii trophozoites than PHMB alone. Fluorescence-activated cell sorting analysis confirmed that HDAC inhibitors increased the apoptotic cell death of Acanthamoeba. Mild CPEs were observed from HCE cells cotreated with PHMB and the HDAC inhibitors after 24 hours of exposure. CONCLUSIONS: Combinatorial treatments showed high amoebicidal effects on Acanthamoeba and low CPEs on HCE cells, which suggests their potential application for Acanthamoeba keratitis treatment.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Biguanidas/farmacologia , Desinfetantes/farmacologia , Epitélio Anterior/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Acanthamoeba castellanii/metabolismo , Anexina A5/metabolismo , Benzamidas/farmacologia , Biguanidas/administração & dosagem , Células Cultivadas , Desinfetantes/administração & dosagem , Sinergismo Farmacológico , Epitélio Anterior/metabolismo , Citometria de Fluxo , Fluoresceína-5-Isotiocianato , Humanos , Ácidos Hidroxâmicos/farmacologia , Microscopia de Fluorescência , Piridinas/farmacologia , Pirróis/farmacologia , Vorinostat/farmacologia
14.
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
15.
Eur J Med Chem ; 188: 111991, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31883490

RESUMO

Semisynthetic 18ß-glycyrrhetinic acid (GA) analogues bearing 1-en-2-cyano-3-oxo substitution on ring A have enhanced antitumor effects with reduced levels of HDAC3 and HDAC6 proteins. Aiming to inhibit both HDAC protein and activity, we developed a hybrid molecule by tethering active GA analogue methyl 2-cyano-3,11-dioxo-18ß-olean-1,12-dien-30-oate (CDODA-Me) and Vorinostat (SAHA). We tested the proper hybrid approaches of GA with hydroxamic acid and turned out that GA conjugated with SAHA by a piperazine linker was the best. The conjugate (15) of CDODA-Me and SAHA linked through a piperazine group was a potent cytotoxic agent against cancer cells with apoptosis induction. Compound 15 was more effective than the simple combination of CDODA-Me and SAHA to induce apoptosis. Mechanistic studies revealed that 15 was less effective than SAHA to inhibit HDAC activity, but was more effective than CDODA-Me to decrease the levels of HDAC3 and HDAC6 proteins with upregulated levels of acetylated H3 and acetylated α-tubulin. Compound 15 represents a new HDAC3 and HDAC6 inhibitor by reducing protein levels.


Assuntos
Antineoplásicos/farmacologia , Ácido Glicirretínico/análogos & derivados , Desacetilase 6 de Histona/metabolismo , Vorinostat/análogos & derivados , Vorinostat/farmacologia , Acetilação , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Glicirretínico/farmacocinética , Ácido Glicirretínico/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Masculino , Ratos Sprague-Dawley , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Vorinostat/farmacocinética
16.
Cells ; 8(12)2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766421

RESUMO

Atypical epigenetic processes including histone acetylation and DNA methylation have been identified as a fundamental theme in hematologic malignancies. Such mechanisms modify gene expression and prompt, in part at least, the initiation and progression of several malignancies including acute myeloid leukemia. In the current study we determined the effects of treating KG-1 and U937 acute myeloid leukemia (AML) cells, in vitro, with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), or with a DNMT inhibitor, decitabine (DAC), or their combination, on cell proliferation, cell cycle progression, apoptosis, and expression of apoptosis-related proteins. Each of SAHA and DAC attenuated cell proliferation and induced cell cycle arrest and apoptotic cell death of KG-1 and U937 cell lines. Besides, their sequential combination improved the obtained anti-neoplastic effect: significant augmentation of growth inhibition and apoptosis induction as compared to cells treated with either drug alone. This effect was featured by the upregulated expression of Bax, cytochrome c1, p21, and cleaved caspases 8, 9, and 3, signifying the activation of both the intrinsic and extrinsic pathways of apoptosis. The sequential combination of SAHA and DAC causes a profound antitumorigenic effect in AML cell lines by inducing the expression of tumor suppressor genes.


Assuntos
Decitabina/farmacologia , Leucemia Mieloide Aguda/terapia , Vorinostat/farmacologia , Adjuvantes Farmacêuticos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Epigênese Genética/genética , Inibidores de Histona Desacetilases/farmacologia , Humanos , Leucemia Mieloide Aguda/genética , Células U937
17.
Hum Mol Genet ; 28(24): 4089-4102, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31691806

RESUMO

A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.


Assuntos
Histona Desmetilases/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Animais , Caenorhabditis elegans , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Feminino , Células HEK293 , Inibidores de Histona Desacetilases/farmacologia , Histona Desmetilases/genética , Histonas/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais , Fatores de Transcrição/metabolismo , Vorinostat/farmacologia
18.
PLoS One ; 14(11): e0224879, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31710657

RESUMO

The latent cellular reservoir of HIV is recognized as the major barrier to cure from HIV infection. Long non-coding RNAs (lncRNAs) are more tissue and cell type-specific than protein coding genes, and may represent targets of choice for HIV latency reversal. Using two in vitro primary T-cell models, we identified lncRNAs dysregulated in latency. PVT1 and RP11-347C18.3 were up-regulated in common between the two models, and RP11-539L10.2 was down-regulated. The major component of the latent HIV reservoir, memory CD4+ T-cells, had higher expression of these lncRNAs, compared to naïve T-cells. Guilt-by-association analysis demonstrated that lncRNAs dysregulated in latency were associated with several cellular pathways implicated in HIV latency establishment and maintenance: proteasome, spliceosome, p53 signaling, and mammalian target of rapamycin (MTOR). PVT1, RP11-347C18.3, and RP11-539L10.2 were down-regulated by latency reversing agents, suberoylanilide hydroxamic acid and Romidepsin, suggesting that modulation of lncRNAs is a possible secondary mechanism of action of these compounds. These results will facilitate prioritization of lncRNAs for evaluation as targets for HIV latency reversal. Importantly, our study provides insights into regulatory function of lncRNA during latent HIV infection.


Assuntos
HIV-1/genética , RNA Longo não Codificante/genética , Latência Viral/genética , Depsipeptídeos/farmacologia , Regulação para Baixo/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Memória Imunológica , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Linfócitos T/imunologia , Latência Viral/efeitos dos fármacos , Vorinostat/farmacologia
19.
Nat Commun ; 10(1): 5052, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699992

RESUMO

To understand the impact of epigenetics on human misfolding disease, we apply Gaussian-process regression (GPR) based machine learning (ML) (GPR-ML) through variation spatial profiling (VSP). VSP generates population-based matrices describing the spatial covariance (SCV) relationships that link genetic diversity to fitness of the individual in response to histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants in the NPC1 gene that disrupt cholesterol homeostasis leading to the rapid onset and progression of neurodegenerative disease. We determine the sequence-to-function-to-structure relationships of the NPC1 polypeptide fold required for membrane trafficking and generation of a tunnel that mediates cholesterol flux in late endosomal/lysosomal (LE/Ly) compartments. HDACi treatment reveals unanticipated epigenomic plasticity in SCV relationships that restore NPC1 functionality. GPR-ML based matrices capture the epigenetic processes impacting information flow through central dogma, providing a framework for quantifying the effect of the environment on the healthspan of the individual.


Assuntos
Colesterol/metabolismo , Fibroblastos/metabolismo , Metabolismo dos Lipídeos/genética , Proteína C1 de Niemann-Pick/genética , Doença de Niemann-Pick Tipo C/genética , Linhagem Celular Tumoral , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Epigênese Genética , Epigenômica , Fibroblastos/efeitos dos fármacos , Células HeLa , Inibidores de Histona Desacetilases/farmacologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Aprendizado de Máquina , Proteína C1 de Niemann-Pick/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Distribuição Normal , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Análise de Regressão , Relação Estrutura-Atividade , Vorinostat/farmacologia
20.
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
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