RESUMO
Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Inibidores de Histona Desacetilases/classificação , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/enzimologia , Neoplasias da Mama/imunologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Neoplasias Pulmonares/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/citologia , Camundongos , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Fagocitose/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologiaRESUMO
In mammalian cloning by somatic cell nuclear transfer (SCNT), the treatment of reconstructed embryos with histone deacetylase (HDAC) inhibitors improves efficiency. So far, most of those used for SCNT are hydroxamic acid derivatives-such as trichostatin A-characterized by their broad inhibitory spectrum. Here, we examined whether mouse SCNT efficiency could be improved using chlamydocin analogues, a family of newly designed agents that specifically inhibit class I and IIa HDACs. Development of SCNT-derived embryos in vitro and in vivo revealed that four out of five chlamydocin analogues tested could promote the development of cloned embryos. The highest pup rates (7.1-7.2%) were obtained with Ky-9, similar to those achieved with trichostatin A (7.2-7.3%). Thus, inhibition of class I and/or IIa HDACs in SCNT-derived embryos is enough for significant improvements in full-term development. In mouse SCNT, the exposure of reconstructed oocytes to HDAC inhibitors is limited to 8-10 h because longer inhibition with class I inhibitors causes a two-cell developmental block. Therefore, we used Ky-29, with higher selectivity for class IIa than class I HDACs for longer treatment of SCNT-derived embryos. As expected, 24-h treatment with Ky-29 up to the two-cell stage did not induce a developmental block, but the pup rate was not improved. This suggests that the one-cell stage is a critical period for improving SCNT cloning using HDAC inhibitors. Thus, chlamydocin analogues appear promising for understanding and improving the epigenetic status of mammalian SCNT-derived embryos through their specific inhibitory effects on HDACs.
Assuntos
Inibidores de Histona Desacetilases/química , Técnicas de Transferência Nuclear/instrumentação , Oócitos/química , Animais , Inibidores de Histona Desacetilases/classificação , Camundongos , Peptídeos Cíclicos/químicaRESUMO
Acetylation of lysine residues within nucleosomal histone tails provides a crucial mechanism for epigenetic control of gene expression. Acetyl groups are coupled to lysine residues by histone acetyltransferases (HATs) and removed by histone deacetylases (HDACs), which are also commonly referred to as "writers" and "erasers", respectively. In addition to altering the electrostatic properties of histones, lysine acetylation often creates docking sites for bromodomain-containing "reader" proteins. This review focuses on epigenetic control of pulmonary hypertension (PH) and associated right ventricular (RV) cardiac hypertrophy and failure. Effects of small molecule HDAC inhibitors in pre-clinical models of PH are highlighted. Furthermore, we describe the recently discovered role of bromodomain and extraterminal (BET) reader proteins in the control of cardiac hypertrophy, and provide evidence suggesting that one member of this family, BRD4, contributes to the pathogenesis of RV failure. Together, the data suggest intriguing potential for pharmacological epigenetic therapies for the treatment of PH and right-sided heart failure.
Assuntos
Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/classificação , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Hipertensão Pulmonar/enzimologia , Hipertrofia Ventricular Direita/enzimologia , Acetilação , Animais , Modelos Animais de Doenças , Epigênese Genética , Humanos , Lisina , RatosRESUMO
A histone deacetylase (HDAC)-based yeast assay employing a URA3 reporter gene was applied as a primary screen to evaluate a marine-derived actinomycete extract library and identify human class III HDAC (SIRT) inhibitors. On the basis of the bioassay-guided purification, a new compound designated as streptosetin A (1) was obtained from one of the active strains identified through the yeast assay. The gross structure of the new compound was elucidated from the 1D and 2D NMR data. The absolute stereostructure of 1 was determined based on X-ray crystal structure analysis and simulation of ECD spectra using time-dependent density functional theory calculations. This compound showed weak inhibitory activity against yeast Sir2p and human SIRT1 and SIRT2.
Assuntos
Actinobacteria/química , Inibidores de Histona Desacetilases/isolamento & purificação , Inibidores de Histona Desacetilases/farmacologia , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Tetra-Hidronaftalenos/isolamento & purificação , Tetra-Hidronaftalenos/farmacologia , Cristalografia por Raios X , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/classificação , Humanos , Biologia Marinha , Conformação Molecular , Estrutura Molecular , Pirrolidinonas/química , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Estereoisomerismo , Tetra-Hidronaftalenos/química , Fatores de TempoRESUMO
Despite the clear progress achieved in recent years in the treatment of MM, most patients eventually relapse and therefore novel therapeutic options are still necessary for these patients. In this regard, several drugs that target specific mechanisms of the tumor cells are currently being explored in the preclinical and clinical setting. This manuscripts offers a review of the rationale and current status of the antimyeloma activity of one of the most relevant examples of these targeted drugs: deacetylase inhibitors (DACi). Several studies have demonstrated the prooncogenic activity of deacetylases (DACs) through the targeting not only of histones but also of non histone proteins relevant to tumor progression, such as p53, E2F family members, Bcl-6, Hsp90, HIF-1α or Nur77. This fact together with the DACs overexpression present in several tumors, has prompted the development of some DACi with potential antitumor effect. This situation is also evident in the case of MM as two mechanisms of DACi, the inhibition of the epigenetic inactivation of p53 and the blockade of the unfolded protein response, through the inhibition of the aggressome formation (by targeting DAC6) and the inactivation of the chaperone system (by acetylating HSP-90), provides the rationale for the exploration of the potential antimyeloma activity of these compounds. Several DACi with different chemical structure and different selectivity for targeting the DAC families have been tested in MM. Their preclinical activity in monotherapy has been quite exciting and has been described to be mediated by various mechanisms: the induction of apoptosis and cell cycle arrest mainly by the upregulation of p21; the interferece with the interaction between plasma cells and the microenvironment, by reducing the expression and signalling of several cytokines or by inhibiting angiogenesis. Finally they also have a role in protecting murine models from myeloma bone disease. Neverteless, the clinical activity in monotherapy of these drugs in relapsed/refractory MM patients has been very modest. This has prompted the development of combinations such as the one with bortezomib or lenalidomide and dexamethasone, which have already been taken into the clinics with positive preliminary results.
Assuntos
Histona Desacetilases/metabolismo , Mieloma Múltiplo/enzimologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Histona Desacetilases/classificação , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/classificação , Humanos , Mieloma Múltiplo/tratamento farmacológicoRESUMO
Pancreatic carcinoma is one of the leading causes of cancer death. Current standard treatments include surgical resection, chemotherapy and radiotherapy but patient's prognosis remains poor and present severe side-effects. Contemporary oncology found a wide variety of novel anticancer drugs that regulate the epigenetic mechanisms of tumor genesis. Histone deacetylases (HDACs) are enzymes with pleiotropic activities that control critical functions of the cell through regulation of the acetylation states of histone proteins and other non-histone protein targets. They are divided into four groups, each with different localization in the cell, role and structure. Histone deacetylase inhibitors (HDACIs) are substances, which inhibit the function of HDACs. We recognize four leading groups (hydroxamic acid, cyclic tetrapeptide, benzamide, aliphatic acid). There are many HDACIs currently in pre-clinical and two (vorinostat, romidepsin) in clinical stages of investigation for pancreatic cancer. Numerous studies argue for the use HDACIs as monotherapy, others suggest that combination of HDACIs with other antitumor drugs has better therapeutic results. This review focuses on the use of HDACIs as novel anticancer drugs and will explain the mechanisms of therapeutic effect on pancreatic cancer.
Assuntos
Carcinogênese/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Benzamidas/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Histona Desacetilases/classificação , Histona Desacetilases/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias Pancreáticas/patologiaRESUMO
Histone deacetylases (HDACs) play a major role in chromatin remodeling, gene regulation, and cellular signaling. While the role of each class of HDAC during normal development is unclear, several HDAC inhibitors are embryotoxic; the mechanisms leading to the teratogenicity of HDAC inhibitors are not known. Here, we investigated the effects of class-specific HDAC inhibitors on the development of organogenesis-stage murine limbs. Timed-pregnant COL2A1-ECFP, COL10A1-mCherry, and COL1A1-YFP CD1 reporter mice were euthanized on gestation day 12; embryonic forelimbs were excised and cultured in vitro for 1, 3, and 6 days in the presence or absence of MS275 (a class I HDAC inhibitor), MC1568 (a class III HDAC inhibitor), Sirtinol (a class II HDAC inhibitor), or valproic acid, our positive control. Fluorescently tagged COL2A1, COL10A1, and COL1A1 served as markers of the differentiation of proliferative chondrocytes, hypertrophic chondrocytes, and osteoblasts, respectively. MS275 and valproic acid caused a reduction in expression of all three markers, suggesting effects on both chondrogenesis and osteogenesis. MC1568 had no effect on chondrocyte markers and mildly inhibited COL1A1 expression at 6 days. Sirtinol had no effect on COL2A1 expression or chondrocyte differentiation 1 day following exposure; however, it caused a drastic regression in limb cartilage and reduced the expression of all three differentiation markers to nearly undetectable levels at 6 days. MS275 and Sirtinol caused a 2.2- and 2.7-fold increase, respectively, in cleaved-caspase 3, a marker of apoptosis, suggesting embryotoxicity. These data demonstrate that inhibition of class I or III HDACs causes severe developmental toxicity and is highly teratogenic.
Assuntos
Apoptose/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inibidores de Histona Desacetilases/toxicidade , Osteogênese/efeitos dos fármacos , Teratogênicos/toxicidade , Animais , Benzamidas/classificação , Benzamidas/toxicidade , Biomarcadores/metabolismo , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Membro Anterior , Genes Reporter/efeitos dos fármacos , Inibidores de Histona Desacetilases/classificação , Ácidos Hidroxâmicos/classificação , Ácidos Hidroxâmicos/toxicidade , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos Transgênicos , Naftóis/classificação , Naftóis/toxicidade , Gravidez , Piridinas/classificação , Piridinas/toxicidade , Pirróis/classificação , Pirróis/toxicidade , Proteínas Recombinantes de Fusão/metabolismo , Teratogênicos/classificaçãoRESUMO
BACKGROUND: Histone deacetylase (HDAC) inhibitors have shown promise in the treatment of resistant and refractory tumors including neuroblastoma. The goal of the study was to compare the efficacy of a class III HDAC inhibitor (cambinol) to a class I and II inhibitor (vorinostat). METHODS: In vitro efficacy of vorinostat and cambinol, alone or in combination with doxorubicin, was assessed by 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide calorimetric assay using both wild-type (WT) and doxorubicin-resistant (DoxR) SK-N-SH neuroblastoma cells. In vivo efficacy was determined using the same drug combinations in nude mice bearing xenograft implants of WT and DoxR cells on opposite flanks. RESULTS: Vorinostat and cambinol were efficacious against WT and DoxR neuroblastoma cells in vitro. In WT cells, the potency of the doxorubicin itself overshadowed any effect of cotherapy with vorinostat or cambinol. The effect of vorinostat and/or cambinol on the DoxR cells was constant across progressively increasing doses of doxorubicin. In the in vivo model, the efficacy of doxorubicin itself (88% reduction in tumor volume) again overshadowed any effect of cotreatment with vorinostat or cambinol on the WT tumors. However, in the DoxR tumors, doxorubicin alone had no efficacy, but cotreatment with either cambinol or vorinostat suppressed tumor growth (70% and 91% reduction in tumor volume, respectively). CONCLUSIONS: Both the class III HDAC inhibitor cambinol and the class I/II HDAC inhibitor vorinostat have efficacy against SK-N-SH neuroblastoma cells, including those resistant to doxorubicin.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Naftalenos/uso terapêutico , Neuroblastoma/tratamento farmacológico , Pirimidinonas/uso terapêutico , Animais , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/classificação , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/farmacologia , Camundongos , Camundongos Nus , Naftalenos/administração & dosagem , Naftalenos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Neuroblastoma/patologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , Ensaio Tumoral de Célula-Tronco , Vorinostat , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in gene expression within the cells (osteoclasts, osteoblasts, and osteocytes) responsible for skeletal maintenance. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Key roles for several Hdacs in bone development and biology have been elucidated though in vitro and in vivo models. Recent findings suggest that clinical usage of small molecule Hdac inhibitors for conditions like epilepsy, bipolar disorder, cancer, and a multitude of other ailments may have unintended effects on bone cell populations. Here we review the progress that has been made in the last decade in understanding how Hdacs contribute to bone development and maintenance.
Assuntos
Desenvolvimento Ósseo/fisiologia , Osso e Ossos/enzimologia , Histona Desacetilases/metabolismo , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Desenvolvimento Ósseo/genética , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Inibidores de Histona Desacetilases/classificação , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Humanos , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/enzimologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/enzimologia , Ratos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Acetylation of histone and non-histone proteins alters gene expression and induces a host of cellular effects. The acetylation process is homeostatically balanced by two groups of cellular enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HAT activity relaxes the structure of the human chromatin, rendering it transcriptionally active, thereby increasing gene expression. In contrast, HDAC activity leads to gene silencing. The enzymatic balance can be 'tipped' by histone deacetylase inhibitors (HDACi), leading to an accumulation of acetylated proteins, which subsequently modify cellular processes including stem cell differentiation, cell cycle, apoptosis, gene expression, and angiogenesis. There is a variety of natural and synthetic HDACi available, and their pleiotropic effects have contributed to diverse clinical applications, not only in cancer but also in non-cancer areas, such as chronic inflammatory disease, bone engineering, and neurodegenerative disease. Indeed, it appears that HDACi-modulated effects may differ between 'normal' and transformed cells, particularly with regard to reactive oxygen species accumulation, apoptosis, proliferation, and cell cycle arrest. The potential beneficial effects of HDACi for health, resulting from their ability to regulate global gene expression by epigenetic modification of DNA-associated proteins, also offer potential for application within restorative dentistry, where they may promote dental tissue regeneration following pulpal damage.
Assuntos
Acetilação/efeitos dos fármacos , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/enzimologia , Inibidores de Histona Desacetilases/farmacologia , Inflamação/enzimologia , Regeneração/genética , Animais , Apoptose , Calcificação Fisiológica/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Polpa Dentária/irrigação sanguínea , Polpa Dentária/citologia , Dentina Secundária/metabolismo , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/classificação , Humanos , NF-kappa B/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco/efeitos dos fármacosRESUMO
Colorectal cancer metastatic recurrence and chemoresistance are major causes of morbidity and mortality. Colon cancer initiating cells (CCIC) are thought to contribute to both these processes. To identify drugs with anti-CCIC activity we screened a number of FDA approved and investigational compounds. We found that the class I selective histone deacetylase inhibitor (HDACi) MGCD0103 has significant activity against CCIC, and also significantly inhibits non-CCIC CRC cell xenograft formation. Both MGCD0103 and the pan-HDAC inhibitor Trichostatin impairs CCIC clonogenicity and cause cell cycle arrest and cell death. Gene expression profiling revealed that the canonical WNT ligand DKK-1 is a highly upregulated target of HDAC inhibitors. Despite the presence of APC mutations and constitutive WNT signaling in CCIC, both transfected and recombinant DKK-1 dramatically inhibit CCIC proliferation and clonogenicity. Overall, these data show that inhibition of class I HDACs is a promising novel approach to target both CCIC and non-CCIC CRC cells. Our studies also provide novel insights into roles for DKK1 in addition to canonical WNT signaling and the mechanism of CCIC tumor formation.