RESUMO
Histone deacetylases (HDACs) are zinc-dependent deacetylases that remove acetyl groups from lysine residues of histones or form protein complexes with other proteins for transcriptional repression, changing chromatin structure tightness, and inhibiting gene expression. Recent in vivo and in vitro studies have amply demonstrated the critical role of HDACs in the cell biology of the nervous system during both physiological and pathological processes and have provided new insights into the conduct of research on neurological disease targets. In addition, in vitro and in vivo studies on HDAC inhibitors show promise for the treatment of various diseases. This review summarizes the regulatory mechanisms of HDAC and the important role of its downstream targets in nervous system diseases, and summarizes the therapeutic mechanisms and efficacy of HDAC inhibitors in various nervous system diseases. Additionally, the current pharmacological situation, problems, and developmental prospects of HDAC inhibitors are described. A better understanding of the pathogenic mechanisms of HDACs in the nervous system may reveal new targets for therapeutic interventions in diseases and help to relieve healthcare pressure through preventive measures.
Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases , Doenças do Sistema Nervoso , Humanos , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Animais , Histona Desacetilases/metabolismo , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/enzimologiaRESUMO
Cardiovascular disease (CVD) has now become the leading cause of death worldwide, and its high morbidity and mortality rates pose a great threat to society. Although numerous studies have reported the pathophysiology of CVD, the exact pathogenesis of all types of CVD is not fully understood. Therefore, much more research is still needed to explore the pathogenesis of CVD. With the development of proteomics, many studies have successfully identified the role of posttranslational modifications in the pathogenesis of CVD, including key processes such as apoptosis, cell metabolism, and oxidative stress. In this review, we summarize the progress in the understanding of posttranslational modifications in cardiovascular diseases, including novel protein posttranslational modifications such as succinylation and nitrosylation. Furthermore, we summarize the currently identified histone deacetylase (HDAC) inhibitors used to treat CVD, providing new perspectives on CVD treatment modalities. We critically analyze the roles of posttranslational modifications in the pathogenesis of CVD-related diseases and explore future research directions related to posttranslational modifications in cardiovascular diseases.
Assuntos
Doenças Cardiovasculares , Processamento de Proteína Pós-Traducional , Humanos , Doenças Cardiovasculares/metabolismo , Animais , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Estresse Oxidativo/fisiologiaRESUMO
Adult T-cell leukemia/lymphoma (ATL) develops from the infection of T cells with human T lymphotropic virus type 1 (HTLV-1). There are an estimated 5-20 million HTLV-1 carriers worldwide and the patients are frequently observed in subtropical Africa, the Caribbean, Middle East, South America, and South West Japan. The prognosis of ATL remains dismal due to rapid acquired resistance to treatment with cytotoxic chemotherapeutic agents. In particular, the development of novel therapies for relapsed or refractory (R/R) ATL is an unmet need. Previous clinical trials revealed that bendamustine (BDM) was effective as the first-line treatment for indolent lymphoma and R/R cases of diffuse large B-cell lymphoma. Its major advantage is that it has few side effects such as hair loss and peripheral neuropathy, and does not impair the quality of life. However, its efficacy has not been verified for ATL in pre-clinical or clinical studies. In this study, we have shown the cytotoxicity of BDM alone and in combination with novel agents including the histone deacetylase (HDAC) inhibitor tucidinostat, the enhancer of zeste homolog 1/2 (EZH1/2) dual inhibitor valemetostat, and the Bcl2 family inhibitor ABT-737. The combined in vitro effects of BDM and tucidinostat were reproduced in a murine model without any obvious hematological toxicity. Our present results suggest that the combination of tucidinostat and BDM could additively prolong the survival of patients with R/R progressive ATL. The efficacy and safety of this combination are thus worthy of investigation in clinical settings.
Assuntos
Cloridrato de Bendamustina , Leucemia-Linfoma de Células T do Adulto , Cloridrato de Bendamustina/uso terapêutico , Cloridrato de Bendamustina/farmacologia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/patologia , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Apoptose/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.
Assuntos
Antineoplásicos , DNA (Citosina-5-)-Metiltransferase 1 , Inibidores de Histona Desacetilases , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/síntese química , Animais , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Histona Desacetilases/metabolismo , Proliferação de Células/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , FemininoRESUMO
The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.
Assuntos
Aminopiridinas , Benzamidas , Linfócitos T CD8-Positivos , Infecções por HIV , HIV-1 , Inibidores de Histona Desacetilases , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Infecções por HIV/imunologia , Infecções por HIV/genética , Aminopiridinas/farmacologia , Feminino , Adulto , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Pessoa de Meia-Idade , HIV-1/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Antígeno B7-H1/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Latência Viral/efeitos dos fármacos , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Macrophage-based cell therapies have shown modest success in clinical trials, which can be attributed to their phenotypic plasticity, where transplanted macrophages get reprogrammed towards a pro-tumor phenotype. In most tumor types, including melanoma, the balance between antitumor M1-like and tumor-promoting M2-like macrophages is critical in defining the local immune response with a higher M1/M2 ratio favoring antitumor immunity. Therefore, designing novel strategies to increase the M1/M2 ratio in the TME has high clinical significance and benefits macrophage-based cell therapies. METHODS: In this study, we reprogrammed antitumor and proinflammatory macrophages ex-vivo with HDAC6 inhibitors (HDAC6i). We administered the reprogrammed macrophages intratumorally as an adoptive cell therapy (ACT) in the syngeneic SM1 murine melanoma model and patient-derived xenograft bearing NSG-SGM3 humanized mouse models. We phenotyped the tumor-infiltrated immune cells by flow cytometry and histological analysis of tumor sections for macrophage markers. We performed bulk RNA-seq profiling of murine bone marrow-derived macrophages treated with vehicle or HDAC6i and single-cell RNA-seq profiling of SM1 tumor-infiltrated immune cells to determine the effect of intratumor macrophage ACT on the tumor microenvironment (TME). We further analyzed the single-cell data to identify key cell-cell interactions and trajectory analysis to determine the fate of tumor-associated macrophages post-ACT. RESULTS: Macrophage ACT resulted in diminished tumor growth in both mouse models. We also demonstrated that HDAC6 inhibition in macrophages suppressed the polarization toward tumor-promoting phenotype by attenuating STAT3-mediated M2 reprogramming. Two weeks post-transplantation, ACT macrophages were viable, and inhibition of HDAC6 rendered intratumor transplanted M1 macrophages resistant to repolarization towards protumor M2 phenotype in-vivo. Further characterization of tumors by flow cytometry, single-cell transcriptomics, and single-cell secretome analyses revealed a significant enrichment of antitumor M1-like macrophages, resulting in increased M1/M2 ratio and infiltration of CD8 effector T-cells. Computational analysis of single-cell RNA-seq data for cell-cell interactions and trajectory analyses indicated activation of monocytes and T-cells in the TME. CONCLUSIONS: In summary, for the first time, we demonstrated the potential of reprogramming macrophages ex-vivo with HDAC6 inhibitors as a viable macrophage cell therapy to treat solid tumors.
Assuntos
Macrófagos , Melanoma , Animais , Camundongos , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Linhagem Celular Tumoral , Microambiente Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Reprogramação Celular , Modelos Animais de DoençasRESUMO
Post-traumatic stress disorder (PTSD) presents distinct sex-specific differences in both symptom expression and treatment outcomes, with the underlying biological mechanisms still remain unclear. Epigenetic modifications, particularly histone acetylation, have been increasingly recognized as critical factors in the pathophysiology of PTSD. Valproic acid (VPA), a potent histone deacetylase (HDAC) inhibitor, has shown promise in modulating epigenetic responses and improving therapeutic outcomes is PTSD, though its effect may differ between sexes. This study aimed to explore the sex-specific epigenetic changes in response to trauma and the impact of VPA treatment in a rat model of PTSD induced by predator scent stress. Sprague-Dawley rats of both sexes were randomly assigned to stressed and non-stressed groups and treated with either VPA (100 mg/kg) or vehicle. Anxiety levels were assessed using the elevated plus maze, followed by analysis of histone H3 and H4 acetylation, HDAC activity, and c-fos expression in the hippocampus. Our findings revealed that traumatic stress led to increased freezing time and anxiety levels, with more pronounced effects observed in females. Additionally, we have identified sex-specific differences in hippocampal epigenetic modifications; stressed females exhibited higher H3 acetylation, and VPA-treated stressed males showed increased H4 acetylation. These results highlight the importance of considering sex differences in the epigenetic mechanism underlying PTSD and suggest that personalized therapeutic approaches may be necessary to address these complexities.
Assuntos
Epigênese Genética , Inibidores de Histona Desacetilases , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos , Ácido Valproico , Animais , Ácido Valproico/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo , Masculino , Feminino , Epigênese Genética/efeitos dos fármacos , Ratos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Modelos Animais de Doenças , Histonas/metabolismo , Caracteres Sexuais , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Ansiedade/tratamento farmacológicoRESUMO
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1+ ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1+ ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).
Assuntos
Benzamidas , Piridinas , Rabdomiossarcoma , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Piridinas/farmacologia , Piridinas/uso terapêutico , Animais , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Camundongos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma/metabolismo , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
Hypoxic-ischemic encephalopathy (HIE) is a brain injury induced by many causes of cerebral tissue ischemia and hypoxia. Although HIE may occur at many ages, its impact on the neonatal brain is greater because it occurs during the formative stage. Recent research suggests that histone modifications may occur in the human brain in response to acute stress events, resulting in transcriptional changes and HIE development. Because there are no safe and effective therapies for HIE, researchers have focused on HIE treatments that target histone modifications. In this review, four main histone modifications are explored, histone methylation, acetylation, phosphorylation, and crotonylation, as well as their relevance to HIE. The efficacy of histone deacetylase inhibitors in the treatment of HIE is also explored. In conclusion, targeting histone modifications may be a novel strategy for elucidating the mechanism of HIE, as well as a novel approach to HIE treatment.
Assuntos
Inibidores de Histona Desacetilases , Histonas , Hipóxia-Isquemia Encefálica , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/terapia , Humanos , Animais , Histonas/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Processamento de Proteína Pós-Traducional , AcetilaçãoRESUMO
Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.
Assuntos
Aminopiridinas , Antineoplásicos , Inibidores de Histona Desacetilases , Pirimidinas , Humanos , Animais , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Aminopiridinas/farmacologia , Aminopiridinas/síntese química , Aminopiridinas/química , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Camundongos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Descoberta de Drogas , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Camundongos Endogâmicos BALB C , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos NusRESUMO
Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.
Assuntos
Cardiotônicos , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Piridinas , Humanos , Animais , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Piridinas/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Relação Estrutura-Atividade , Cardiotônicos/farmacologia , Cardiotônicos/química , Cardiotônicos/síntese química , Cardiotônicos/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Masculino , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Imidazóis/uso terapêutico , Camundongos Nus , Descoberta de DrogasRESUMO
HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 µM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.
Assuntos
Antineoplásicos , Neoplasias da Mama , Inibidores de Histona Desacetilases , Histona Desacetilases , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite considerable research efforts, inflammatory diseases remain a heavy burden on human health, causing significant economic losses annually. Histone deacetylases (HDACs) play a significant role in regulating inflammation (via histone and non-histone protein deacetylation) and chromatin structure and gene expression regulation. Herein, we present a detailed description of the different HDACs and their functions and analyze the role of HDACs in inflammatory diseases, including pro-inflammatory cytokine production reduction, immune cell function modulation, and anti-inflammatory cell activity enhancement. Although HDAC inhibitors have shown broad inflammatory disease treatment potentials, their clinical applicability remains limited because of their non-specific effects, adverse effects, and drug resistance. With further research and insight, these inhibitors are expected to become important tools for the treatment of a wide range of inflammatory diseases. This review aims to explore the mechanisms and application prospects of HDACs and their inhibitors in multiple inflammatory diseases.
Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases , Inflamação , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Humanos , Histona Desacetilases/metabolismo , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: Oesophageal cancer remains a challenging disease with high mortality rates and few therapeutic options. In view of these difficulties, epigenetic drugs have emerged as potential alternatives for patient care. The goal of this study was to evaluate the effect and biological consequences of Panobinostat treatment, an HDAC (histone deacetylase) inhibitor already approved for treatment of patients with multiple myeloma, in oesophageal cell lines of normal and malignant origin, with the latter being representative of the two main histological subtypes: adenocarcinoma and squamous cell carcinoma. RESULTS: Panobinostat treatment inhibited growth and hindered proliferation, colony formation and invasion of oesophageal cancer cells. Considering HDAC tissue expression, HDAC1 was significantly upregulated in normal oesophageal epithelium in comparison with tumour tissue, whereas HDAC3 was overexpressed in oesophageal cancer compared to non-malignant mucosa. No differences between normal and tumour tissue were observed for HDAC2 and HDAC8 expression. CONCLUSIONS: Panobinostat exposure effectively impaired malignant features of oesophageal cancer cells. Because HDAC3 was shown to be overexpressed in oesophageal tumour samples, this epigenetic drug may represent an alternative therapeutic option for oesophageal cancer patients.
Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Proliferação de Células , Neoplasias Esofágicas , Inibidores de Histona Desacetilases , Histona Desacetilases , Panobinostat , Humanos , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Panobinostat/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Linhagem Celular Tumoral , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Proliferação de Células/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Proteínas Repressoras/genética , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologiaRESUMO
Breast cancer, a heterogeneous and intricate disease, ranks among the leading causes of mortality in women. Restricted therapeutic choices, drug resistance, recurrence, and metastasis are the predominant conditions that lead to mortality. Accumulating evidence has shown breast cancer initiation and progression happen through a multifaceted and intricate process that involves numerous genetic and epigenetic alterations. The modulation of gene expression through epigenetic modifications, encompassing DNA methylation, histone alterations, and non-coding RNA regulation, has emerged as a fascinating field that represents a new avenue for breast cancer therapy. This review emphasizes various aberrant epigenetic regulations implicated in the onset and advancement of breast cancer. The critical epigenetic modifications closely associated with estrogen signaling, epithelial-to-mesenchymal transition (EMT), cancer stemness, and drug resistance have been discussed extensively. Moreover, it highlights current epi-drugs, including DNA modifying agents, histone acetyltransferase inhibitors, histone deacetylase inhibitors, histone methyltransferase inhibitors, and histone demethyltransferase inhibitors used for breast cancer treatment. Nonetheless, we described current investigations pertaining to combination therapy employing epi-drugs and future challenges.
Assuntos
Neoplasias da Mama , Metilação de DNA , Epigênese Genética , Transição Epitelial-Mesenquimal , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Transição Epitelial-Mesenquimal/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/uso terapêuticoRESUMO
Hepatocellular carcinoma (HCC) is the primary malignant tumor of the liver. c-Myc is one of the most common oncogenes in clinical settings, and amplified levels of c-Myc are frequently found in HCC. Histone deacetylase inhibitors (HDACi), such as Trichostatin A (TSA), hold enormous promise for the treatment of HCC. However, the potential and mechanism of TSA in the treatment of c-Myc-induced HCC are unclear. In this study, we investigated the effects of TSA treatment on a c-Myc-induced HCC model in mice. TSA treatment delayed the development of HCC, and liver function indicators such as ALT, AST, liver weight ratio, and spleen weight ratio demonstrated the effectiveness of TSA treatment. Oil red staining further demonstrated that TSA attenuated lipid accumulation in the HCC tissues of mice. Through mRNA sequencing, we identified that TSA mainly affected cell cycle and fatty acid degradation genes, with alcohol dehydrogenase 4 (ADH4) potentially being the core molecular downstream target. QPCR, immunohistochemistry, and western blot analysis revealed that ADH4 expression was repressed by c-Myc and restored after TSA treatment both in vitro and in vivo. Furthermore, we observed that the levels of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration increased after c-Myc transfection in liver cells but decreased after TSA intervention. The levels of phosphorylated protein kinase B (p-AKT) and p-mTOR were identified as targets regulated by TSA, and they governed the ADH4 expression and the downstream regulation of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration. Overall, our study suggests that TSA has a therapeutic effect on c-Myc-induced HCC through the AKT-mTOR-ADH4 pathway. These findings provide valuable insights into the potential treatment of HCC using TSA and shed light on the underlying molecular mechanisms involved.
Assuntos
Carcinoma Hepatocelular , Ácidos Hidroxâmicos , Neoplasias Hepáticas , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-myc , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Álcool Desidrogenase/metabolismo , Álcool Desidrogenase/genética , Masculino , Progressão da Doença , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Bcell lymphoma is difficult to cure because of its biological and clinical heterogeneity, and due to native chemoresistance. Immunotherapies that overcome cancerinduced immune evasion have been the center of recent developments in oncology. This is emphasized by the accomplishment of various agents that disrupt programmed cell death protein 1 (PD1)mediated immune suppression in diverse tumors. However, while PD1 blockade has been effective in numerous malignancies, a significant proportion of cancers, including Bcell lymphoma, show certain rates of primary resistance to these therapeutic strategies. Histone deacetylase inhibitors (HDACis) have exhibited anticancer activity though suppressing cell proliferation, inducing differentiation and triggering apoptosis. The present study aimed to explore a therapeutic strategy combining a HDACi (romidepsin) and PD1 blockade (BMS1) in Bcell lymphoma, utilizing a constructed mouse model of Bcell lymphoma. The IC50 of the two inhibitors was confirmed by MTT assay, and their inhibitory effects were revealed to be dose and timedependent. The data demonstrated that the combined treatment of romidepsin and BMS1 synergistically inhibited the growth of Bcell lymphoma. Furthermore, it was revealed that romidepsin and BMS1 synergistically triggered apoptosis in mouse Bcell lymphoma. The synergistic effect of these agents was capable of activating tumorinfiltrating lymphocytes, particularly CD3+CD4+ and CD3+CD8+ T cells. The results of the present study underscore the potential of HDAC inhibition in conjunction with PD1 blockade as a novel therapeutic approach for Bcell lymphoma, highlighting the synergistic effects of these two mechanisms in enhancing antitumor immunity.
Assuntos
Apoptose , Depsipeptídeos , Sinergismo Farmacológico , Inibidores de Histona Desacetilases , Linfoma de Células B , Receptor de Morte Celular Programada 1 , Animais , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Depsipeptídeos/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Humanos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Modelos Animais de Doenças , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Progressão da Doença , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC), ranking as the fourth most prevalent cancer globally, has garnered significant attention due to its high invasiveness and mortality rates. However, drug therapies face challenges of inadequate efficacy and unclear mechanisms. Here, we propose a novel biohybrid hydrogel that targets ß-klotho (KLB) for HCC treatment. As a dual-network hydrogel, this gel combines gelatin methacryloyl (GelMA) and polyvinyl alcohol (PVA) to ensure biocompatibility while enhancing controlled drug release. Notably, it exhibits good storage stability, high drug load capacity, and efficient water absorption. By introducing the HDAC3 inhibitor RGFP966, we can selectively inhibit the activation of KLB. This deactivation effectively blocks the FGF21-KLB signaling pathway and inhibits the progression of HCC. Importantly, we have successfully validated this unique phenomenon both in vivo and in vitro, providing substantial evidence for the efficacy of this hydrogel-based anti-tumor drug delivery system as a promising strategy for HCC treatment. This innovative research outcome brings new hope to the field of tumor therapy, providing a reliable theoretical foundation for future clinical applications.
Assuntos
Carcinoma Hepatocelular , Histona Desacetilases , Hidrogéis , Proteínas Klotho , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Humanos , Histona Desacetilases/metabolismo , Hidrogéis/química , Animais , Camundongos , Linhagem Celular Tumoral , Álcool de Polivinil/química , Transdução de Sinais/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêuticoRESUMO
Mutations in the γ-amino butyric acid type A (GABAA) receptor γ2 subunit gene, GABRG2, have been associated with refractory epilepsy. Increasing evidence indicates that suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone acetyltransferases (HDACs) inhibitor, can inhibit seizure onset. However, the mechanisms involved remains unknown. The present study aimed to explore the anti-epileptic effect and underlying mechanisms of SAHA in the treatment of refractory epilepsy induced by GABRG2 mutation. In the zebrafish line expressing human mutant GABRG2(F343L), Tg(hGABRG2F343L), SAHA was found to reduce seizure onset, swimming activity, and neuronal activity. In both Tg(hGABRG2F343L) zebrafish and HEK293T cells transfected with GABAA receptor subunits, SAHA could improve the pan-acetylation level and reduce the expression of HDAC1/10. The decreased expressions of GABAA receptor subunits could be rescued by SAHA treatment both in vivo and in vitro, which might be the result of increased gene transcription and protein trafficking. The up-regulated acetylation of histone H3 and H4 as well as Bip expression might be involved in the process. Taken together, our data proved that both histone and non-histone acetylation might contribute to the anti-epileptic effect of SAHA in refractory epilepsy caused by GABRG2(F343L) mutation, demonstrating SAHA as a promising therapeutic agent for refractory epilepsy.
Assuntos
Mutação , Receptores de GABA-A , Vorinostat , Peixe-Zebra , Animais , Humanos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Células HEK293 , Vorinostat/farmacologia , Vorinostat/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/genética , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Animais Geneticamente ModificadosRESUMO
The genetic era has opened the opportunity of using personalized therapeutic approaches, in part based on targeting genes with somatic mutations. For example, lymphomas harboring the highly recurrent CREBBP mutation show dependency on HDAC3, thus selective inhibition of HDAC3 reversed the epigenetic effects of CREBBP mutation, halted lymphoma growth, and induced MHC class II expression, enabling the T-cells to recognize and kill lymphoma cells. However, CREBBP wild type (WT) cells are less sensitive to this approach. In this issue of Leukemia, He et al. have executed a genome-wide CRISPR screening that identified GNAS as a target to maximize the therapeutic activity of HDAC3 inhibition in CREBBP WT lymphoma.