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1.
Int J Mol Sci ; 23(7)2022 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-35409342

RESUMO

Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns.


Assuntos
Inibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Ligantes , Conformação Molecular , Relação Estrutura-Atividade
2.
Molecules ; 27(8)2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35458704

RESUMO

Curcumin is an anti-inflammatory and neuroprotective compound in turmeric. It is a potential ligand of the aryl hydrocarbon receptor (AhR) that mediates anti-inflammatory signaling. However, the AhR-mediated anti-inflammatory effect of curcumin within the brain remains unclear. We investigated the role of AhR on the curcumin effect in inflammatory astrogliosis. Curcumin attenuated lipopolysaccharide (LPS)-induced proinflammatory IL-6 and TNF-α gene expression in primary cultured rat astrocytes. When AhR was knocked down, LPS-induced IL-6 and TNF-α were increased and curcumin-decreased activation of the inflammation mediator NF-κB p65 by LPS was abolished. Although LPS increased AhR and its target gene CYP1B1, curcumin further enhanced LPS-induced CYP1B1 and indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan to AhR ligands kynurenine (KYN) and kynurenic acid (KYNA). Potential interactions between curcumin and human AhR analyzed by molecular modeling of ligand-receptor docking. We identified a new ligand binding site on AhR different from the classical 2,3,7,8-tetrachlorodibenzo-p-dioxin site. Curcumin docked onto the classical binding site, whereas KYN and KYNA occupied the novel one. Moreover, curcumin and KYNA collaboratively bound onto AhR during molecular docking, potentially resulting in synergistic effects influencing AhR activation. Curcumin may enhance the inflammation-induced IDO/KYN axis and allosterically regulate endogenous ligand binding to AhR, facilitating AhR activation to regulate inflammatory astrogliosis.


Assuntos
Curcumina , Gliose , Receptores de Hidrocarboneto Arílico , Animais , Curcumina/farmacologia , Gliose/tratamento farmacológico , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interleucina-6 , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Ligantes , Lipopolissacarídeos , Simulação de Acoplamento Molecular , Ratos , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Necrose Tumoral alfa/genética
3.
Toxicology ; 472: 153191, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35489423

RESUMO

The present study investigated the attenuating effects of Zn following Cd-exposure in the activities/expression of indoleamine 2, 3-dioxygenase (IDO), tryptophan 2, 3-dioxygenase (TDO), oxidative-inflammatory response, behavioral indices and histologic architecture in cerebral cortex and hippocampus of male rats. Adult male Wistar rats were exposed to 200 µg/L and 100 µg/L of Cd and/or Zn in drinking water for 42 days. Cd exposure significantly increased IDO and TDO activities, IDO 1 protein expression, inflammatory response, with attendant disruption in antioxidant systems and concomitant elevation in malondialdehyde (MDA) levels in the cerebral cortex and hippocampus. Following Zn co-treatment, Cd-mediated increase in IDO 1 protein expression, IDO, and TDO activities, and decrease in antioxidant enzymes, and an increase in markers of inflammatory response and MDA production were significantly (p < 0.05) reversed compared with control. Moreover, altered behavioral indices and histological architecture of brain sections following Cd exposure was evidently (p < 0.05) prevented by Zn co-treatment relative to control. Overall, Cd-induced alterations in IDO 1 expression, IDO and TDO activities, oxidative-inflammatory response, behavioral indices, and histological architecture in the cerebral cortex and hippocampus of rats within the time course of the investigation were prevented by Zn co-treatment.


Assuntos
Fármacos Neuroprotetores , Triptofano , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Cádmio/toxicidade , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Ratos , Ratos Wistar , Triptofano/farmacologia , Zinco/farmacologia
4.
Nutrients ; 14(7)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35406118

RESUMO

Prostate cancer (PC) is the second leading cause of death in men in the US. PC has a high recurrence rate, and limited therapeutic options are available to prevent disease recurrence. The tryptophan-degrading enzymes 2,3-indoleamine dioxygenase (IDO1) and tryptophan dioxygenase (TDO2) are upregulated in invasive PC. (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (ß-CBT) and its C-4 epimer α-CBT are the precursors to key flavor ingredients in tobacco leaves. Nearly 40-60% of ß- and α-CBT are purposely degraded during commercial tobacco fermentation. Earlier, ß-CBT inhibited invasion, reversed calcitonin-stimulated transepithelial resistance decrease, and induced tighter intercellular barriers in PC-3M cells. This study demonstrates the in vitro ß-CBT anti-migratory (wound-healing assay) and anti-clonogenicity (colony-formation assay) activities against five diverse human PC cell lines, including the androgen-independent PC-3, PC-3M, and DU-145, the castration-recurrent CWR-R1ca, and the androgen-dependent CWR-22rv1. Meanwhile, ß-CBT potently suppressed in vivo locoregional and distant recurrences after the primary tumor surgical excision of PC-3M-Luc cell tumor engrafted in male nude mice. ß-CBT treatments suppressed organ and bone metastasis and lacked any major toxicity over the 60-day study course. ß-CBT treatments significantly suppressed IDO1, TDO2, and their final metabolite kynurenine levels in PC-3M cells. ß-CBT treatments significantly suppressed the tumor recurrence marker PSA and kynurenine levels in treated animals' plasma. ß-CBT emerges as a promising PC recurrence suppressive lead.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase , Neoplasias da Próstata , Triptofano Oxigenase , Androgênios , Animais , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Masculino , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia , Estudos Prospectivos , Tabaco , Triptofano Oxigenase/metabolismo
5.
Front Immunol ; 13: 832989, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35371018

RESUMO

Several serine proteases have been linked to autoimmune disorders and tumour initiation although the mechanisms are not fully understood. Activation of the kynurenine pathway enzyme indoleamine-2,3-dioxygenase (IDO1) modulates cellular activity in the brain, tolerogenesis in the immune system and is a major checkpoint in cancer development. We now report that IDO1 mRNA and IDO1 protein expression (generating kynurenine) are induced in human monocyte-derived macrophages by several chymotryptic serine proteases with direct links to tumorigenesis, including Prostate Specific Antigen (PSA), CD26 (Dipeptidyl-peptidase-4, CD26/DPP-4), High Temperature Requirement protein-A (HtrA), and the bacterial virulence factor subtilisin. These proteases also induce expression of the pro-inflammatory cytokine genes IL1B and IL6. Other serine proteases tested: bacterial glu-C endopeptidase and mammalian Pro-protein Convertase Subtilase-Kexin-3 (PCSK3, furin), urokinase plasminogen activator (uPA), cathepsin G or neutrophil elastase, did not induce IDO1, indicating that the reported effects are not a general property of all serine proteases. The results represent a novel mechanism of activating immunosuppressive IDO1 and inducing kynurenine generation which, together with the production of inflammatory cytokines, would contribute to tumour initiation and progression, providing a new target for drug development. In addition, the proteasomal S20 serine protease inhibitor carfilzomib, used in the treatment of myeloma, prevented the induction of IDO1 and cytokine gene expression, potentially contributing to its clinical anti-cancer activity.


Assuntos
Cinurenina , Neoplasias , Animais , Citocinas , Dipeptidil Peptidase 4/genética , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Masculino , Mamíferos/metabolismo , Antígeno Prostático Específico , Serina Proteases , Proteína Estafilocócica A , Subtilisina
6.
Front Immunol ; 13: 832263, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35371054

RESUMO

The indoleamine 2,3-dioxygenase 1 (IDO1) metabolic circuitry, comprising the first tryptophan (Trp) catabolite L-kynurenine (Kyn) and the aryl hydrocarbon receptor (AHR), has emerged as a mechanism of cancer immune evasion. Here, we investigated the functional role of the IDO1/Kyn/AHR axis in chronic lymphocytic leukemia (CLL). Our data show that CLL cells expressed an active form of the IDO1 enzyme and microenvironmental stimuli can positively modulate its expression. Interferon (IFN)-γ induces IDO1 expression through the Jak/STAT1 pathway and mediates Kyn production concomitantly with Trp consumption in CLL-conditioned media, while INCB018424 (ruxolitinib), a JAK1/2 inhibitor, impaired both effects. To characterize the involvement of IDO1 in leukemic cell maintenance, we overexpressed IDO1 by vector transfection measuring enhanced resistance to spontaneous apoptosis. IDO1 pro-survival influence was confirmed by treating CLL cells with Kyn, which mediated the increase of induced myeloid leukemia cell differentiation protein (MCL1). Conversely, AHR silencing or its blockade via CH-223191 improved the apoptosis of leukemic clones and mitigated MCL1 expression. Moreover, Kyn-treated CLL cells are less affected by the pro-apoptotic effect of ABT-199 (venetoclax), while CH-223191 showed synergistic/additive cytotoxicity with this drug. Lastly, targeting directly MCL1 in CLL cells with AMG-176, we abrogate the pro-survival effect of Kyn. In conclusion, our data identify IDO1/Kyn/AHR signaling as a new therapeutic target for CLL, describing for the first time its role in CLL pathobiology.


Assuntos
Cinurenina , Leucemia Linfocítica Crônica de Células B , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo
7.
Sci Transl Med ; 14(636): eabg8402, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35294258

RESUMO

To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD+), which reduced T cell proliferation and function. Because NAD+ metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD+ on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD+-mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase , Neoplasias Ovarianas , Animais , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Ativação Linfocitária , Camundongos , NAD , Neoplasias Ovarianas/tratamento farmacológico , Triptofano/metabolismo , Microambiente Tumoral
8.
Curr Med Sci ; 42(2): 407-416, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35235132

RESUMO

OBJECTIVE: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), causes an estimated 1.6 million human deaths annually, but the pathogenesis of TB remains unclear. Immunity plays a critical role in the onset and outcome of TB. This study aimed to uncover the roles of innate and adaptive immunity in TB. METHODS: The gene expression profiles generated by RNA sequencing from human peripheral blood mononuclear cells (PBMCs) stimulated with or without Mtb strain H37Rv antigens were analyzed. A total of 973 differentially expressed mRNAs were identified. RESULTS: The differentially expressed genes were enriched in innate immunity signaling functions. The mesenchymal-epithelial transition factor (MET) gene was significantly upregulated in CD14+ monocytes. A MET inhibitor improved the uptake of the BCG strain by monocytes and macrophages as well as inhibited the expression of indoleamine 2,3-dioxygenase (IDO). The expression of IDO was increased in PBMCs stimulated with Mtb antigens, and the IDO inhibitor promoted the expression of CD40, CD83, and CD86. CONCLUSION: Our results might provide clues regarding the immunomodulatory mechanisms used by Mtb to evade the host defense system.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Leucócitos Mononucleares/metabolismo , Monócitos/metabolismo , Tuberculose/genética , Tuberculose/metabolismo
9.
J Med Chem ; 65(8): 6001-6016, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35239336

RESUMO

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.


Assuntos
Inibidores Enzimáticos , Éteres Cíclicos , Amidas , Ciclização , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
10.
Cell Rep ; 38(10): 110462, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263589

RESUMO

Nociceptors can fine-tune local or systemic immunity, but the mechanisms of nociceptive modulation in endotoxic death remain largely unknown. Here, we identified C-type lectin Reg3γ as a nociceptor-enriched hormone that protects the host from endotoxic death. During endotoxemia, nociceptor-derived Reg3γ penetrates the brain and suppresses the expression of microglial indoleamine dioxygenase 1, a critical enzyme of the kynurenine pathway, via the Extl3-Bcl10 axis. Endotoxin-administered nociceptor-null mice and nociceptor-specific Reg3γ-deficient mice exhibit a high mortality rate accompanied by decreased brain HK1 phosphorylation and ATP production despite normal peripheral inflammation. Such metabolic arrest is only observed in the brain, and aberrant production of brain quinolinic acid, a neurotoxic metabolite of the kynurenine pathway, causes HK1 suppression. Strikingly, the central administration of Reg3γ protects mice from endotoxic death by enhancing brain ATP production. By identifying nociceptor-derived Reg3γ as a microglia-targeted hormone, this study provides insights into the understanding of tolerance to endotoxic death.


Assuntos
Cinurenina , Microglia , Proteínas Associadas a Pancreatite/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Endotoxinas/metabolismo , Hormônios/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Camundongos , Microglia/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Nociceptores/metabolismo
12.
Nature ; 603(7902): 721-727, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35264796

RESUMO

Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme1-4. Here we show that despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process, and pinpointed tryptophanyl-tRNA synthetase (WARS1) as its source. We call these W>F peptides 'substitutants' to distinguish them from genetically encoded mutants. Using large-scale proteomics analyses, we demonstrate W>F substitutants to be highly abundant in multiple cancer types. W>F substitutants were enriched in tumours relative to matching adjacent normal tissues, and were associated with increased IDO1 expression, oncogenic signalling and the tumour-immune microenvironment. Functionally, W>F substitutants can impair protein activity, but also expand the landscape of antigens presented at the cell surface to activate T cell responses. Thus, substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.


Assuntos
Triptofano-tRNA Ligase , Triptofano , Códon/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interferon gama , Neoplasias/imunologia , Fenilalanina , Linfócitos T , Triptofano/metabolismo , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo , Triptofano-tRNA Ligase/genética , Triptofano-tRNA Ligase/metabolismo
13.
Cytokine ; 152: 155832, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35202987

RESUMO

Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (pAPCs), numerous in the pancreas of nonobese diabetic (NOD) mice and playing an essential role in the autoimmune response of type 1 diabetes. The expression of the enzyme indoleamine 2,3-dioxygenase (IDO) is a critical factor for the tolerogenic activity of pAPCs, acting in the catabolism of tryptophan, providing metabolites that suppress the T cell effectors and induce T regulatory cells differentiation. Here we investigated the in vitro mechanisms of lyophilized aqueous extract from Passiflora alata leaves (LAEPAL) that modulates bone marrow-derived professional antigen-presenting cells (BM-pAPCs), affecting their ability to polarize T cells. A cell culture model was defined using mixed cultures of BM-pAPCs and T lymphocytes NOD mice with stressed MIN-6 cells as a source of pancreatic ß cells antigens. We showed that the treatment with 300 µg/mL of LAEPAL induces a significant decrease in the CD4 and CD8 T effector lymphocytes proliferation from diabetic but not in non-diabetic mice, followed by a reduction of the IL-6 and IFN-γ cytokines release in the cell cultures supernatants. Moreover, we observed an increase of CD4+CD25+FoxP3+ Tregs in the cell cultures from diabetic mice. These results could be partially explained by the LAEPAL modulatory effects in BM-pAPCs, downregulating the CD86 co-stimulatory molecule expression, and increasing IDO-1 expression in F4/80+ BM-pAPCs. These results contribute to a better understanding of the polyphenols' immunomodulatory properties, meaning they could induce tolerogenic antigen-presenting cells, which could polarize T cells to a Treg profile and decrease the activity of CD4+ and CD8+ T effector cells.


Assuntos
Diabetes Mellitus Experimental , Passiflora , Animais , Células Apresentadoras de Antígenos/metabolismo , Antígenos , Antígeno B7-2/metabolismo , Medula Óssea/metabolismo , Células Cultivadas , Células Dendríticas , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Passiflora/metabolismo , Folhas de Planta , Linfócitos T Reguladores
14.
Pharmacol Res ; 177: 106132, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35183714

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in tryptophan catabolism along the kynurenine (Kyn) pathway and exerts immunosuppressive properties mainly via activation of transcription factor aryl hydrocarbon receptor (AhR) pathway. IDO1 induces NK cells dysfunction via downregulation of the activating receptor NKG2D on NK cells, but whether and how it affects the expression of NKG2D Ligand (NKG2DL) on tumor cells remains unclear. Since a disintegrin and metalloprotease 10 (ADAM10) plays a potential role in the shedding of NKG2DL and the releasing of soluble NKG2DL (sNKG2DL), we investigated how IDO1 modulates the expression of NKG2DL via ADAM10 in non-small cell lung cancer (NSCLC). We found that IDO1 expression was negatively correlated with NKG2DL expression while positively correlated with ADAM10 expression with human lung cancer brain metastasis tissue, NSCLC cells and LLC tumor-bearing mice. IDO1 could regulate ADAM10 expression via IDO1-Kyn-AhR signaling pathway and subsequently regulate NKG2DL expression. IDO1 deficiency led to retarded tumor growth and improved NK cells function in NSCLC mice. IDO1 inhibitors improved NK cells function in vitro and in vivo. The combo of IDO1 inhibitor and NK cells exhibited more therapeutic efficacy than either of the single IDO1 inhibitor or NK cells treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Pulmonares , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação para Baixo , Humanos , Células Matadoras Naturais/metabolismo , Cinurenina/metabolismo , Ligantes , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo
15.
Toxicol Appl Pharmacol ; 440: 115921, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35157906

RESUMO

Breast cancer is the primary cause of cancer-related deaths in women. Tamoxifen (TAM) is the preferred drug for treating premenopausal luminal-type breast cancer, but TAM resistance restricts its ability to benefit patients. To date, the mechanism of this resistance remains unclear, and there is currently no effective treatment for reversing it. The expression of indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to be elevated in various malignancies. Here, we aimed to investigate the role of IDO1 in TAM-resistant breast cancer. We confirmed that IDO1 is strongly expressed in TAM-resistant breast cancer, and it mediates drug-resistant cell proliferation, metastasis, and TAM resistance in vivo and in vitro through interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3). We also found that the mechanism by which TAM upregulates IDO1 is dependent on STAT1 activation. In summary, IDO1 regulates TAM resistance and can serve as a novel target for treatment of TAM-resistant breast cancer.


Assuntos
Neoplasias da Mama , Tamoxifeno , Antineoplásicos Hormonais/farmacologia , Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interleucina-6 , Tamoxifeno/farmacologia
16.
Front Immunol ; 13: 818411, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35140722

RESUMO

Background: Inhibitory checkpoints are promising antitumor targets and predictive biomarkers in a variety of cancers. We aimed to identify the expression levels and prognostic value of multiple inhibitory checkpoints supported by preclinical and clinical evidence in head and neck lymphoepithelioma-like carcinoma (HNLELC). Methods: The expression of seven inhibitory checkpoints were evaluated in the tumor nest (TN) and tumor stroma (TS) of 102 HNLELC specimens using immunohistochemistry and digital pathology, and an inhibitory checkpoint-based signature (ICS) was subsequently constructed using the LASSO Cox regression model. Results: PD-L1, B7H3, and IDO-1 were mostly expressed in the TN, with median H-score of TN vs TS: 63.6 vs 14.6; 8.1 vs 1.0; 61.5 vs 34.7 (all P < 0.001), whereas PD-1, TIM-3, LAG-3, and VISTA were mainly observed in the TS, with median H-score of TN vs TS: 0.2 vs 12.4, 3.4 vs 7.1, 6.2 vs 11.9, 16.4 vs 47.2 (all P < 0.001), respectively. The most common simultaneously expressed combinations consisted of PD-L1 + B7H3 + IDO-1 + TIM-3 + LAG-3 + VISTA and B7H3 + IDO-1 + TIM-3 + LAG-3 in the TN (both occurring in 8.8% of patients) and PD-L1 + B7H3 + IDO-1 in the TS (4.9%). In addition, high-ICS patients had shorter 5-year disease-free (40.6% vs 81.7%; P < 0.001), regional recurrence-free (63.5% vs 88.2%; P = 0.003), and overall survival (73.5% vs 92.9%; P = 0.006) than low-ICS patients. Multivariate analysis revealed that ICS represented an independent predictor, which could significantly complement the predictive performance of TNM stage for 3-year (AUC 0.724 vs 0.619, P = 0.014), 5-year (AUC 0.727 vs 0.640, P = 0.056), and 10-year disease-free survival (AUC 0.815 vs 0.709, P = 0.023). Conclusions: The expression of inhibitory checkpoints and ICS classifier may increase the prognostic value of the TNM staging system and guide the rational design of personalized inhibitory checkpoint blockade therapy in HNLELC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/mortalidade , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo
17.
Front Immunol ; 13: 807271, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35173722

RESUMO

Metabolism of tryptophan (Trp), an essential amino acid, represent a major metabolic pathway that both promotes tumor cell intrinsic malignant properties as well as restricts antitumour immunity, thus emerging as a drug development target for cancer immunotherapy. Three cytosolic enzymes, namely indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO2), catalyzes the first-rate limiting step of the degradation of Trp to kynurenine (Kyn) and modulates immunity toward immunosuppression mainly through the aryl hydrocarbon receptor (AhR) activation in numerous types of cancer. By restoring antitumor immune responses and synergizing with other immunotherapies, the encouraging preclinical data of IDO1 inhibitors has dramatically failed to translate into clinical success when combined with immune checkpoints inhibitors, reigniting the debate of combinatorial approach. In this review, we i) provide comprehensive evidences on immunomodulatory role of the Trp catabolism metabolites that highlight this pathway as relevant target in immuno-oncology, ii)ii) discuss underwhelming results from clinical trials investigating efficacy of IDO1 inhibitors and underlying mechanisms that might have contributed to this failure, and finally, iii) discuss the current state-of-art surrounding alternative approaches of innovative antitumor immunotherapies that target molecules of Trp catabolism as well as challenges and perspectives in the era of immunotherapy.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Triptofano Oxigenase/antagonistas & inibidores , Triptofano/metabolismo , Animais , Inibidores Enzimáticos/uso terapêutico , Humanos , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano Oxigenase/metabolismo
18.
Cells ; 11(4)2022 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-35203299

RESUMO

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in the inflammatory response and in the modulation of innate and adaptive immunity, we describe some mechanisms that strongly suggest its involvement in the management of COVID-19's inflammatory framework. It regulates both the expression of Angiotensin Converting Enzyme-2 (ACE-2) and its stabilizing partner, the Broad neutral Amino acid Transporter 1 (B0AT1). It induces Indolamine 2,3 dioxygenase (IDO-1), the enzyme which, starting from Tryptophan (Trp), produces Kynurenine (Kyn, Beta-Anthraniloyl-L-Alanine). The accumulation of Kyn and the depletion of Trp arrest T cell growth and induce apoptosis, setting up an immune-tolerant condition, whereas AhR and interferon type I (IFN-I) build a mutual inhibitory loop that also involves NF-kB and limits the innate response. AhR/Kyn binding boosts the production of Interleukin-6 (IL-6), thus reinforcing the inflammatory state and counteracting the IDO-dependent immune tolerance in the later stage of COVID-19. Taken together, these data depict a framework where sufficient clues suggest the possible participation of AhR in the management of COVID-19 inflammation, thus indicating an additional therapeutic target for this disease.


Assuntos
COVID-19/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , SARS-CoV-2/metabolismo , Imunidade Adaptativa/imunologia , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , COVID-19/imunologia , COVID-19/transmissão , Humanos , Imunidade Inata/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Inflamação/imunologia , Cinurenina/metabolismo , Receptores de Hidrocarboneto Arílico/fisiologia , SARS-CoV-2/patogenicidade , Transdução de Sinais , Triptofano/metabolismo
19.
Anal Biochem ; 645: 114605, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35181297

RESUMO

Kynurenine (Kyn) is involved in a variety of physiological/pathological reactions via activating aryl hydrocarbon receptor (Ahr). However, how to activate Ahr by Kyn under physiological/pathological conditions is still unclear. Here, we presented that Kyn (8 µM, a concentration less than the dose of Kyn-induced Ahr activation) significantly induced the nuclear transfer of Ahr and the expression of cytochrome P450 1A1 (CYP1A1, a classic biomarker for Ahr activation) when co-administered with ultraviolet (UV) irradiation in 95D cells, which were transfected transiently with siRNA against indoleamine 2,3-dioxygenase 1 (IDO 1) and cultured in cell medium supplemented with bovine serum containing bovine serum albumin (BSA), in vitro. Additionally, we found that the fluorescence intensity of BSA was attenuated by Kyn (2, 4, 6, 8, 10, 12 and 14 µM) mainly through quenching the fluorescence of tryptophan (Trp) residues in the pattern of dynamic quenching related to molecular diffusion. More important, resonance energy transfer from excited-state BSA to Kyn was confirmed, leading to the generation "energetic" Kyn that might be ability of hyperactivity according to the theory of photochemical reaction. These data indicate that UV irradiation is contributable for Kyn to function, and present a novel pattern of altering the activity of biomolecules to some degree.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase , Cinurenina , Transferência de Energia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Cinurenina/farmacologia , Triptofano/metabolismo
20.
Mol Biol Rep ; 49(4): 3297-3306, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35028850

RESUMO

The amino acid tryptophan (TRP) is critical for the expansion and survival of cells. During the past few years, the manipulation of tryptophan metabolism via indoleamine 2,3 dioxygenase (IDO) has been presented as a significant regulatory mechanism for tolerance stimulation and the regulation of immune responses. Currently, a considerable number of studies suggest that the role of IDO in T helper 2 (Th2) cell regulation may be different from that of T helper 1 (Th1) immune responses. IDO acts as an immunosuppressive tolerogenic enzyme to decrease allergic responses through the stimulation of the Kynurenine-IDO pathway, the subsequent reduction of TRP, and the promotion of Kynurenine products. Kynurenine products motivate T-cell apoptosis and anergy, the propagation of Treg and Th17 cells, and the aberration of the Th1/Th2 response. We suggest that the IDO-kynurenine pathway can function as a negative reaction round for Th1 cells; however, it may play a different role in upregulating principal Th2 immune responses. In this review, we intend to integrate novel results on this pathway in correlation with allergic diseases.


Assuntos
Hipersensibilidade , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Humanos , Imunidade , Cinurenina/metabolismo , Triptofano/metabolismo
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