RESUMEN
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.
Asunto(s)
Adenocarcinoma , Carcinoma de Células Escamosas , Proliferación Celular , Neoplasias Esofágicas , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Panobinostat , Humanos , Panobinostat/farmacología , Panobinostat/uso terapéutico , Panobinostat/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Línea Celular Tumoral , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Proliferación Celular/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/genética , Proteínas Represoras/genética , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Indoles/farmacología , Indoles/uso terapéutico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patologíaRESUMEN
Purpose: Intravitreal injection of anti-VEGF antibodies remains the primary therapy for exudative age-related macular degeneration (exAMD), although its efficacy is limited. Previous research has demonstrated that both a loss-of-function mutation of srr and the intravenous injection of a serine racemase inhibitor, L-aspartic acid ß-hydroxamate (L-ABH), significantly inhibit laser-induced choroidal neovascularization (CNV) in mice. Given that L-ABH is a small molecule, this study investigated the effects of L-ABH administered via eye drops on CNV, aiming to develop a noninvasive treatment strategy for exAMD. Methods: CNV models in mice and rhesus macaques were established through laser photocoagulation. Seven monkeys were randomly assigned to receive either saline solution or L-ABH eye drops. Intraperitoneal or intravenous injection of fluorescein characterized CNV in both mice and monkeys. Fluorescein fundus angiography was used to assess leakage, whereas optical coherence tomography measured retinal thickness in the monkeys. Results: L-ABH eye drops significantly reduced fluorescein leakage in laser-injured mice (P < 0.001 compared to saline). In laser-injured rhesus macaques, the average percent changes in leakage areas treated with L-ABH were 2.5% ± 25.8% (P = 0.004) and 1.5% ± 75.7% (P = 0.023 compared to saline solution) on day 14 and day 28, respectively. However, L-ABH eye drops did not significantly affect the number of grade IV laser spots or retinal thickness, whereas bevacizumab did. Conclusions: This study demonstrates the potential efficacy of an SRR inhibitor in two animal models of laser-induced CNV. Translational Relevance: This represents the first investigation into the effects of topical delivery of an SRR inhibitor on CNV.
Asunto(s)
Neovascularización Coroidal , Modelos Animales de Enfermedad , Angiografía con Fluoresceína , Macaca mulatta , Ratones Endogámicos C57BL , Tomografía de Coherencia Óptica , Animales , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/patología , Ratones , Racemasas y Epimerasas/antagonistas & inhibidores , Racemasas y Epimerasas/genética , Racemasas y Epimerasas/metabolismo , Coagulación con Láser/efectos adversos , Soluciones Oftálmicas , Masculino , Coroides/efectos de los fármacos , Coroides/patología , Coroides/diagnóstico por imagen , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéuticoRESUMEN
ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) is one of the sub-types of peripheral T-cell lymphomas (PTCLs) that are remarkably refractory and has the potential to have a poor prognosis. The treatment process includes a wide range of treatment modalities, from anthracycline-based regimens that have been used for years to novel agents, such as histone deacetylase inhibitor romidepsin and belinostat. Increased treatment response rates and prolonged survival have been reported in studies with belinostat. Similarly, in this case report, we wanted to share a patient of an advanced age and with a high IPI score, whom we had treated in many treatment lines and maintained a long-term treatment response by administering belinostat.
Asunto(s)
Ácidos Hidroxámicos , Linfoma de Células T Periférico , Sulfonamidas , Humanos , Sulfonamidas/uso terapéutico , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/patología , Ácidos Hidroxámicos/uso terapéutico , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Resultado del Tratamiento , Resistencia a Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Anciano , Antineoplásicos/uso terapéutico , FemeninoRESUMEN
Recent advancements in comprehending peripheral T-cell lymphomas (PTCLs) validate and broaden our perspective, highlighting their diverse nature and the varying molecular mechanisms underlying the entities. Based on a comprehensive accumulated understanding, the PTCLs currently overcome the most challenging features of any disease: rarity, incredible heterogeneity, and a lack of any established standard of care. The treatments deployed in the front-line are extrapolated from regimens developed for other diseases. The recent approval of the three drugs brentuximab vedotin (BV), pralatrexate, and belinostat for patients with relapsed or refractory disease has provided clues about pathophysiology and future directions, though challenges satisfying post-marketing requirements (PMR) for those accelerated approvals have led to one of those drugs being withdrawn and put the other two in jeopardy. Edits of the front-line regimens, often called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-plus approaches, look more like CHOP-minus strategies, as the toxicity of five-drug regimens often reduces the dose intensity of the added 'novel' drug, nullifying any hope of an advance. The turmoil in the field produced by the aforementioned, coupled with an ever-changing classification, has left the field uncertain about the path forward. Despite these challenges, empiric findings from studies of novel drug approaches, coupled with a logic emerging from studies of PTCL lymphomagenesis, have begun to illuminate, albeit faintly for some, a potential direction. The empiric finding that drugs targeting the discrete components of the PTCL epigenome, coupled with the description of multiple mutations in genes that govern epigenetic biology, offers, at the very least, an opportunity to finally be hypothesis-driven. The most recent recognition that the only combination of drugs shown to markedly improve progression-free survival (PFS) in patients with relapsed disease is one based on dual targeting of different and discrete components of that epigenetic biology has established a possibility that circumnavigating chemotherapy addition studies is both plausible, feasible, and likely the best prospect for a quantum advance in this disease. Herein, we analyze PTCL through a 2025 lens, highlighting and underscoring walls that have impeded progress. We will critically explore all the clues and the panoramic view of PTCL research.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotina , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/genética , Brentuximab Vedotina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aminopterina/análogos & derivados , Aminopterina/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Sulfonamidas/uso terapéutico , Ciclofosfamida/uso terapéutico , Vincristina/uso terapéutico , Doxorrubicina/uso terapéuticoRESUMEN
BACKGROUND: Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. METHODS: A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. RESULTS: We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. CONCLUSIONS: Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.
Asunto(s)
Neoplasias de la Mama , Cumarinas , Histona Desacetilasa 1 , Ácidos Hidroxámicos , Transducción de Señal , Cumarinas/química , Cumarinas/farmacología , Humanos , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/genética , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Animales , Transducción de Señal/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/uso terapéutico , Factor de Transcripción Sp1/metabolismo , Ratones , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Descubrimiento de DrogasRESUMEN
BACKGROUND: Lipids, as a fundamental cell component, play an regulating role in controlling the different cellular biological processes involved in viral infections. A notable feature of coronavirus disease 2019 (COVID-19) is impaired lipid metabolism. The function of lipophagy-related genes in COVID-19 is unknown. The present study aimed to investigate biomarkers and drug targets associated with lipophagy and lipophagy-based therapeutic agents for COVID-19 through bioinformatics analysis. METHODS: Lipophagy-related biomarkers for COVID-19 were identified using machine learning algorithms such as random forest, Support Vector Machine-Recursive Feature Elimination, Generalized Linear Model, and Extreme Gradient Boosting in three COVID-19-associated GEO datasets: scRNA-seq (GSE145926) and bulk RNA-seq (GSE183533 and GSE190496). The cMAP database was searched for potential COVID-19 medications. RESULTS: The lipophagy pathway was downregulated, and the lipid droplet formation pathway was upregulated, resulting in impaired lipid metabolism. Seven lipophagy-related genes, including ACADVL, HYOU1, DAP, AUP1, PRXAB2, LSS, and PLIN2, were used as biomarkers and drug targets for COVID-19. Moreover, lipophagy may play a role in COVID-19 pathogenesis. As prospective drugs for treating COVID-19, seven potential downregulators (phenoxybenzamine, helveticoside, lanatoside C, geldanamycin, loperamide, pioglitazone, and trichostatin A) were discovered. These medication candidates showed remarkable binding energies against the seven biomarkers. CONCLUSIONS: The lipophagy-related genes ACADVL, HYOU1, DAP, AUP1, PRXAB2, LSS, and PLIN2 can be used as biomarkers and drug targets for COVID-19. Seven potential downregulators of these seven biomarkers may have therapeutic effects for treating COVID-19.
Asunto(s)
Antivirales , Biomarcadores , Tratamiento Farmacológico de COVID-19 , COVID-19 , Metabolismo de los Lípidos , SARS-CoV-2 , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , SARS-CoV-2/genética , COVID-19/virología , Metabolismo de los Lípidos/efectos de los fármacos , Antivirales/uso terapéutico , Antivirales/farmacología , Biología Computacional/métodos , Aprendizaje Automático , Lactamas Macrocíclicas/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Ácidos Hidroxámicos/farmacología , Benzoquinonas/farmacología , Benzoquinonas/uso terapéuticoRESUMEN
Urothelial carcinoma (UC) urgently requires new therapeutic options. Histone deacetylases (HDAC) are frequently dysregulated in UC and constitute interesting targets for the development of alternative therapy options. Thus, we investigated the effect of the second generation HDAC inhibitor (HDACi) quisinostat in five UC cell lines (UCC) and two normal control cell lines in comparison to romidepsin, a well characterized HDACi which was previously shown to induce cell death and cell cycle arrest. In UCC, quisinostat led to cell cycle alterations, cell death induction and DNA damage, but was well tolerated by normal cells. Combinations of quisinostat with cisplatin or the PARP inhibitor talazoparib led to decrease in cell viability and significant synergistic effect in five UCCs and platinum-resistant sublines allowing dose reduction. Further analyses in UM-UC-3 and J82 at low dose ratio revealed that the mechanisms included cell cycle disturbance, apoptosis induction and DNA damage. These combinations appeared to be well tolerated in normal cells. In conclusion, our results suggest new promising combination regimes for treatment of UC, also in the cisplatin-resistant setting.
Asunto(s)
Apoptosis , Inhibidores de Histona Desacetilasas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Vejiga Urinaria , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Daño del ADN/efectos de los fármacos , Sinergismo Farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patologíaRESUMEN
More attention has been paid to immunotherapy for ovarian cancer and the development of tumor vaccines. We developed a trichostatin A (TSA)-modified tumor vaccine with potent immunomodulating activities that can inhibit the growth of ovarian cancer in rats and stimulate immune cell response in vivo. TSA-treated Nutu-19 cells inactivated by X-ray radiation were used as a tumor vaccine in rat ovarian cancer models. Prophylactic and therapeutic experiments were performed with TSA-modified tumor vaccine in rats. Flow cytometry and ELISpot assays were conducted to assess immune response. Immune cell expression in the spleen and thymus were detected by immunohistochemical staining. GM-CSF, IL-7, IL-17, LIF, LIX, KC, MCP-1, MIP-2, M-CSF, IP-10/CXCL10, MIG/CXCL9, RANTES, IL-4, IFN-γ, and VEGF expressions were detected with Milliplex Map Magnetic Bead Panel immunoassay. TSA vaccination in therapeutic and prophylactic models could effectively stimulate innate immunity and boost the adaptive humoral and cell-mediated immune responses to inhibit the growth and tumorigenesis of ovarian cancer. This vaccine stimulated the thymus into reactivating status and enhanced infiltrating lymphocytes in tumor-bearing rats. The expression of key immunoregulatory factors were upregulated in the vaccine group. The intensities of infiltrating CD4+ and CD8+ T cells and NK cells were significantly increased in the vaccine group compared to the control group (P<0.05). This protection was mainly dependent on the IFN-γ pathway and, to a much lesser extent, by the IL-4 pathway. The tumor cells only irradiated by X-ray as the control group still showed a slight immune effect, indicating that irradiated cells may also cause certain immune antigen exposure, but the efficacy was not as significant as that of the TSA-modified tumor vaccine. Our study revealed the potential application of the TSA-modified tumor vaccine as a novel tumor vaccine against tumor refractoriness and growth. These findings offer a better understanding of the immunomodulatory effects of the vaccine against latent tumorigenesis and progression. This tumor vaccine therapy may increase antigen exposure, synergistically activate the immune system, and ultimately improve remission rates. A vaccine strategy designed to induce effective tumor immune response is being considered for cancer immunotherapy.
Asunto(s)
Vacunas contra el Cáncer , Ácidos Hidroxámicos , Neoplasias Ováricas , Animales , Femenino , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/prevención & control , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Ratas , Ácidos Hidroxámicos/uso terapéutico , Ácidos Hidroxámicos/farmacología , Citometría de Flujo , Línea Celular Tumoral , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE. METHODS: We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution. We proved the involvement of IDO1 and the AHR in SB939-mediated immunosuppression using Ido1-/- and Ahr-/- mice. RESULTS: Administration with SB939 halted EAE progression, which depended upon IDO1 expression in neurons of the central nervous system (CNS). Our in vitro and in vivo studies demonstrated that SB939 sustained the interleukin-6-induced acetylation of STAT3, resulting in the stable transcriptional activation of Ido1. The therapeutic effect of SB939 also required the AHR, which is expressed mainly in CD4+ T cells and macrophages in CNS disease lesions. Finally, SB939 was shown to markedly reduce the proliferation of CD4+ T cells in inflamed neuronal tissues but not in the spleen or draining lymph nodes. CONCLUSIONS: Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4+ T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Inhibidores de Histona Desacetilasas , Indolamina-Pirrol 2,3,-Dioxigenasa , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas , Factor de Transcripción STAT3 , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/metabolismo , Ratones , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Femenino , Médula Espinal/patología , Médula Espinal/metabolismo , Médula Espinal/inmunología , Médula Espinal/efectos de los fármacos , Glicoproteína Mielina-Oligodendrócito/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Progresión de la Enfermedad , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Fragmentos de Péptidos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Interleucina-6/metabolismo , Interleucina-6/genéticaRESUMEN
The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.
Asunto(s)
Apoptosis , Neoplasias Hematológicas , Fenilalanina/análogos & derivados , Tiofenos , Humanos , Apoptosis/efectos de los fármacos , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Citostáticos/farmacología , Proliferación Celular/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Células HL-60 , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patologíaRESUMEN
Histone deacetylase (HDAC) inhibitors are emerging as promising treatments for hematological malignancies, with potential applications extending to solid tumors in the future. Given their wide-ranging biological effects, there is a pressing need for a thorough understanding of the toxicities linked to HDAC inhibition. In this study, a pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System database. Suspected adverse events linked to HDAC inhibitors were detected through various statistical methodologies, including reporting odds ratio, proportional reporting ratio, information component, and Empirical Bayes Geometric Mean. Our study findings have illuminated that, among the total reported cases examined, gastrointestinal disorders accounted for 13% patients of the cohort, while lymphatic system disorders comprised 8% cases of the cohort, all of which manifested as adverse events induced by HDAC inhibitors. Importantly, the usage of HDAC inhibitors was found to be associated with incidents of atrial fibrillation, heart failure, respiratory failure, hepatic dysfunction, and acute kidney injury. Romidepsin and belinostat demonstrated more pronounced signals of adverse events compared to panobinostat and vorinostat, emphasizing the need for vigilant monitoring of adverse events in this particular population. Furthermore, atrial fibrillation (clinical priority score of 7 points) emerged as the paramount medical event warranting utmost clinical attention. Eventually, multiple adverse events were observe to emerge within the initial and second months following the initiation of treatment. Vigilant monitoring and supportive care strategies are critical in addressing the toxicities associated with HDAC inhibitors, particularly those concerning cardiotoxicity, respiratory toxicity, renal toxicity, and hepatotoxicity.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Inhibidores de Histona Desacetilasas , Farmacovigilancia , Humanos , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Vorinostat/efectos adversos , Panobinostat/efectos adversos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/uso terapéutico , Depsipéptidos/efectos adversos , Estados Unidos/epidemiología , Enfermedades Gastrointestinales/inducido químicamente , Teorema de Bayes , Neoplasias Hematológicas/tratamiento farmacológico , Fibrilación Atrial/inducido químicamente , Fibrilación Atrial/tratamiento farmacológico , Adolescente , Adulto Joven , Anciano de 80 o más Años , SulfonamidasRESUMEN
Interleukin-1-beta (IL-1ß) one of the biomarkers for oral squamous cell carcinoma (OSCC), is upregulated in tumor-microenvironment (TME) and associated with poor patient survival. Thus, a novel modulator of IL-1ß would be of great therapeutic value for OSCC treatment. Here we report regulation of IL-1ß and TME by histone deacetylase-6 (HDAC6)-inhibitor in OSCC. We observed significant upregulation of HDAC6 in 4-nitroquniline (4-NQO)-induced OSCC in mice and 4-NQO & Lipopolysaccharide (LPS) stimulated OSCC and fibroblast cells. Tubastatin A (TSA)-attenuated the OSCC progression in mice as observed improvement in the histology over tongue and esophagus, with reduced tumor burden. TSA treatment to 4-NQO mice attenuated protein expression of HDAC6, pro-and-mature-IL-1ß and pro-and-cleaved-caspase-1 and ameliorated acetylated-tubulin. In support of our experimental work, human TCGA analysis revealed HDAC6 and IL-1ß were upregulated in the primary tumor, with different tumor stages and grades. We found TSA modulate TME, indicated by downregulation of CD11b+Gr1+-Myeloid-derived suppressor cells, CD11b+F4/80+CD206+ M2-macrophages and increase in CD11b+F4/80+MHCII+ M1-macrophages. TSA significantly reduced the gene expression of HDAC6, IL-1ß, Arginase-1 and iNOS in isolated splenic-MDSCs. FaDu-HTB-43 and NIH3T3 cells stimulated with LPS and 4-NQO exhibit higher IL-1ß levels in the supernatant. Interestingly, immunoblot analysis of the cell lysate, we observed that TSA does not alter the expression as well as activation of IL-1ß and caspase-1 but the acetylated-tubulin was found to be increased. Nocodazole pre-treatment proved that TSA inhibited the lysosomal exocytosis of IL-1ß through tubulin acetylation. In conclusion, HDAC6 inhibitors attenuated TME and cancer progression through the regulation of IL-1ß in OSCC.
Asunto(s)
Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos , Indoles , Interleucina-1beta , Neoplasias de la Boca , Microambiente Tumoral , Animales , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Interleucina-1beta/metabolismo , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/inmunología , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Ratones , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Ratones Endogámicos C57BL , Línea Celular Tumoral , Progresión de la Enfermedad , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Masculino , Tubulina (Proteína)/metabolismo , LipopolisacáridosRESUMEN
BACKGROUND: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. PATIENTS AND METHODS: Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. RESULTS: Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. CONCLUSIONS: Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2. TRIAL REGISTRATION: NCT03812796 (registered 23rd January 2019).
Asunto(s)
Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Neoplasias Colorrectales , Neoplasias Esofágicas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Femenino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Persona de Mediana Edad , Anciano , Adenocarcinoma/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Reparación de la Incompatibilidad de ADN , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Anciano de 80 o más Años , Ácidos Hidroxámicos/uso terapéutico , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/administración & dosificaciónRESUMEN
Cancer cells can upregulate the MYC expression to repair the radiotherapy-triggered DNA damage, aggravating therapeutic resistance and tumor immunosuppression. Epigenetic treatment targeting the MYC-transcriptional abnormality may intensively solve this clinical problem. Herein, 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) are engineered into a tungsten-based nano-radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity. Individual 5-Aza depletes MYC expression but cannot efficiently awaken radiotherapeutic immunity. This drawback can be overcome by the addition of ITF-2357, which triggers cancer cellular type I interferon (IFN-I) signaling. Coupling 5-Aza with ITF-2357 ensures that PWAI does not evoke the treated model with high MYC-related immune resistance while amplifying the radiotherapeutic tumor killing, and more importantly promotes the generation of IFN-I signal-related proteins involving IFN-α and IFN-ß. Unlike the radiation treatment alone, PWAI-triggered immuno-radiotherapy remarkably enhances antitumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory-phenotype formation in 4T1 tumor-bearing mice. Downgrading the radiotherapy-induced MYC overexpression via the dual-epigenetic reprogramming strategy may elicit a robust immuno-radiotherapy.
Asunto(s)
Epigénesis Genética , Inmunoterapia , Proteínas Proto-Oncogénicas c-myc , Fármacos Sensibilizantes a Radiaciones , Animales , Humanos , Ratones , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Epigénesis Genética/efectos de los fármacos , Terapia de Inmunosupresión/métodos , Inmunoterapia/métodos , Interferón Tipo I/metabolismo , Nanopartículas/química , Neoplasias/terapia , Neoplasias/inmunología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Metilasas de Modificación del ADN/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéuticoRESUMEN
There are more than 240 million cases of malaria and 600,000 associated deaths each year, most due to infection with Plasmodium falciparum parasites. While malaria treatment options exist, new drugs with novel modes of action are needed to address malaria parasite drug resistance. Protein lysine deacetylases (termed HDACs) are important epigenetic regulatory enzymes and prospective therapeutic targets for malaria. Here we report the antiplasmodial activity of a panel of 17 hydroxamate zinc binding group HDAC inhibitors with alkoxyamide linkers and different cap groups. The two most potent compounds (4a and 4b) were found to inhibit asexual P. falciparum growth with 50% inhibition concentrations (IC50's) of 0.07 µM and 0.09 µM, respectively, and demonstrated >200-fold more selectivity for P. falciparum parasites versus human neonatal foreskin fibroblasts (NFF). In situ hyperacetylation studies demonstrated that 4a, 4b and analogs caused P. falciparum histone H4 hyperacetylation, suggesting HDAC inhibition, with structure activity relationships providing information relevant to the design of new Plasmodium-specific aliphatic chain hydroxamate HDAC inhibitors.
Asunto(s)
Antimaláricos , Malaria Falciparum , Malaria , Parásitos , Animales , Recién Nacido , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/uso terapéutico , Malaria/tratamiento farmacológico , Plasmodium falciparum , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Antimaláricos/uso terapéuticoRESUMEN
Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.
Asunto(s)
Androstenos , Neoplasias Encefálicas , Glioblastoma , Esteroide 17-alfa-Hidroxilasa , Animales , Humanos , Ratones , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Daño del ADN , Resistencia a Antineoplásicos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Histona Desacetilasa 6/genética , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estrés Oxidativo , Temozolomida/farmacología , Temozolomida/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Histone deacetylase inhibitors not only possess favorable effects on modulating tumor microenvironment and host immune cells but also can reactivate the genes silenced due to deacetylation and chromatin condensation. Hydroxamic acid hybrids as promising histone deacetylase inhibitors have the potential to address drug resistance and reduce severe side effects associated with a single drug molecule due to their capacity to simultaneously modulate multiple targets in cancer cells. Accordingly, rational design of hydroxamic acid hybrids may provide valuable therapeutic interventions for the treatment of breast cancer. This review aimed to provide insights into the in vitro and in vivo anti-breast cancer therapeutic potential of hydroxamic acid hybrids, together with their mechanisms of action and structure-activity relationships, covering articles published from 2020 to the present.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Relación Estructura-Actividad , Microambiente TumoralRESUMEN
Histone deacetylases (HDACs) are commonly overexpressed in several types of human cancers, including prostate cancer (PCa). Histone deacetylase inhibitors (HDACis) are emerging as promising tools for cancer therapy. However, there is still a need to understand their anti-tumor effects and the mechanisms underlying their action. In our study, we investigated the effects of co-treatment with CUDC-101 and docetaxel (DTX) on cell growth, clonogenicity, invasion and migration of PCa cells both in vitro, and in a xenograft mouse model. We found that the combination of CUDC-101 and DTX significantly reduced tumor growth, as evidenced by lower tumor weight and volumes. Moreover, apoptotic cell death was increased in the combination group compared to either drug alone or control. Mechanistically, we observed that the combined treatment of CUDC-101 with DTX suppressed the progression of PCa cell lines through the AKT and ERK1/2 signaling pathways. Additionally, this combination treatment reversed EMT by modulating the expression of key markers such as E-cadherin, vimentin, Snail and MMP-9. To conclude, these results demonstrated that the combination of CUDC-101 with DTX had a synergistic and significantly improved anti-carcinogenic effect. This combination may serve as a potential strategy for clinical treatment and prognosis improvement in PCa.
Asunto(s)
Ácidos Hidroxámicos , Neoplasias de la Próstata , Masculino , Humanos , Animales , Ratones , Docetaxel/farmacología , Línea Celular Tumoral , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Apoptosis , Proliferación CelularRESUMEN
Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDAC inhibitors have failed to provide substantial clinical benefit to patients with glioblastoma (GBM) to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. Although no isoform-specific HDAC inhibitors are currently available, the second-generation hydroxamic acid-based HDAC inhibitor quisinostat possesses subnanomolar specificity for class I HDAC isoforms, particularly HDAC1 and HDAC2. It has been shown that HDAC1 is the essential HDAC in GBM. This study analyzed the neuropharmacokinetic, pharmacodynamic, and radiation-sensitizing properties of quisinostat in preclinical models of GBM. It was found that quisinostat is a well-tolerated and brain-penetrant molecule that extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Niño , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Histona Desacetilasas/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Isoformas de Proteínas/metabolismo , Encéfalo/metabolismoRESUMEN
Toxoplasmosis is a critical health issue for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii that is found worldwide. Although efficient drugs are commonly used to treat toxoplasmosis, serious adverse events are common. Therefore, new compounds with potent anti-T. gondii activity are needed to provide better suited treatments. We have tested compounds designed to target specifically histone deacetylase enzymes. Among the 55 compounds tested, we identified three compounds showing a concentration of drug required for 50% inhibition (IC50) in the low 100 nM range with a selectivity index of more than 100. These compounds are not only active at inhibiting the growth of the parasite in vitro but also at preventing some of the consequences of the acute disease in vivo. Two of these hydroxamate based compound also induce a hyper-acetylation of the parasite histones while the parasitic acetylated tubulin level remains unchanged. These findings suggest that the enzymes regulating histone acetylation are potent therapeutic targets for the treatment of acute toxoplasmosis.