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1.
Cancer Sci ; 112(9): 3856-3870, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288281

RESUMO

Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and epidermal growth factor receptor (EGFR) inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of BRAF inhibitor dabrafenib (DAB) and MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Reverse-phase protein array analysis revealed that proteins with altered phosphorylation induced by miR-193a-3p were involved in several oncogenic pathways including MAPK-related pathways. Furthermore, overexpression of miR-193a-3p in BRAF-mutated cells enhanced the efficacy of DAB and TRA through inhibiting reactivation of MAPK signaling and inducing inhibition of Mcl1. Inhibition of Mcl1 by siRNA or by Mcl1 inhibitor increased the antiproliferative effect of combination therapy with DAB, TRA, and anti-EGFR antibody cetuximab. Collectively, our study demonstrated the possibility that miR-193a-3p acts as a tumor suppressor through regulating multiple proteins involved in oncogenesis and affects cellular sensitivity to MAPK-related pathway inhibitors such as BRAF inhibitors, MEK inhibitors, and/or anti-EGFR antibodies. Addition of miR-193a-3p and/or modulation of proteins involved in the miR-193a-3p-mediated pathway, such as Mcl1, to EGFR/BRAF/MEK inhibition may be a potential therapeutic strategy against BRAF-mutated CRC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Genes Supressores de Tumor , Imidazóis/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Oximas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacologia , Pirimidinonas/farmacologia , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Cetuximab/farmacologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Quimioterapia Combinada/métodos , Receptores ErbB/antagonistas & inibidores , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transfecção
2.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204776

RESUMO

Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. The molecular mechanisms underlying muscle dysfunction in this disease remain unclear. Here, we observed that this mutation causes an abnormally high Ca2+-sensitivity of myofilaments in vitro and in muscle fibers. To determine the critical conformational changes that myosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changes caused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90P mutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which is accompanied by the almost complete depression of troponin's ability to switch actin monomers off and to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca2+. These changes in the behavior of tropomyosin and the troponin-tropomyosin complex, as well as in the balance of strongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of both abnormally high Ca2+-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity, and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca2+-dependent movement and the ability of the troponin-tropomyosin complex to switch actin monomers off, demonstrating a weakening of the damaging effect of the R90P mutation on muscle contractility.


Assuntos
Contração Muscular/genética , Mutação/genética , Oximas/farmacologia , Sulfonamidas/farmacologia , Tropomiosina/genética , Actinas/metabolismo , Animais , Cálcio/metabolismo , Contração Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Miofibrilas/efeitos dos fármacos , Miofibrilas/metabolismo , Miosinas/metabolismo , Coelhos , Troponina/metabolismo
3.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298919

RESUMO

This study was conducted to investigate doubled haploid (DH) lines produced between high GSL (HGSL) Brassica rapa ssp. trilocularis (yellow sarson) and low GSL (LGSL) B. rapa ssp. chinensis (pak choi) parents. In total, 161 DH lines were generated. GSL content of HGSL DH lines ranged from 44.12 to 57.04 µmol·g-1·dry weight (dw), which is within the level of high GSL B. rapa ssp. trilocularis (47.46 to 59.56 µmol g-1 dw). We resequenced five of the HGSL DH lines and three of the LGSL DH lines. Recombination blocks were formed between the parental and DH lines with 108,328 single-nucleotide polymorphisms in all chromosomes. In the measured GSL, gluconapin occurred as the major substrate in HGSL DH lines. Among the HGSL DH lines, BrYSP_DH005 had glucoraphanin levels approximately 12-fold higher than those of the HGSL mother plant. The hydrolysis capacity of GSL was analyzed in HGSL DH lines with a Korean pak choi cultivar as a control. Bioactive compounds, such as 3-butenyl isothiocyanate, 4-pentenyl isothiocyanate, 2-phenethyl isothiocyanate, and sulforaphane, were present in the HGSL DH lines at 3-fold to 6.3-fold higher levels compared to the commercial cultivar. The selected HGSL DH lines, resequencing data, and SNP identification were utilized for genome-assisted selection to develop elite GSL-enriched cultivars and the industrial production of potential anti-cancerous metabolites such as gluconapin and glucoraphanin.


Assuntos
Brassica rapa/genética , Glucosinolatos/genética , Brassica rapa/efeitos dos fármacos , Genótipo , Glucosinolatos/farmacologia , Haploidia , Isotiocianatos/farmacologia , Oximas/farmacologia , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Sulfóxidos/farmacologia
4.
J Agric Food Chem ; 69(29): 8098-8109, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34278787

RESUMO

To explore natural-product-based pesticidal candidates and high value-added application of cholesterol in agriculture, oximinoether derivatives of cholesterol-containing isoxazoline/isoxazole fragments (I-1∼I-16 and II-1∼II-18) were semiprepared by structural optimization of cholesterol. Their structures were characterized by optical rotation, high-resolution mass spectrometry (HRMS), IR, and 1H NMR spectroscopy. Particularly, the Z configurations of oxime fragments at the C-7 position of target compounds were undoubtedly determined by X-ray crystallography. Against Mythimna separata Walker, compounds 3e, I-8, I-14, and II-3 showed 2.4-2.7-fold growth inhibitory activity of the precursor cholesterol. Against Plutella xylostella Linnaeus, compounds I-6, I-7, and I-9 showed 2.4-2.7-fold oral toxicity of cholesterol. Against Aphis citricola Van der Goot, compounds 2e and II-15 exhibited 4.9 and 5.8-fold aphicidal activity of cholesterol, respectively. Notably, they showed good control effects (3.0-5.0-fold promising control efficiency of 1) against A. citricola in the greenhouse. Structure-activity relationships (SARs) suggested that the C-3 hydroxyl group and the C-7 position of cholesterol are two important modification sites. It will pave the way for future structural optimization and application of cholesterol derivatives as potential pesticidal agents in agriculture.


Assuntos
Inseticidas , Mariposas , Agricultura , Animais , Colesterol , Éter , Inseticidas/farmacologia , Isoxazóis/farmacologia , Estrutura Molecular , Oximas/farmacologia , Relação Estrutura-Atividade
5.
J Med Chem ; 64(13): 9444-9457, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34138573

RESUMO

Screening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.


Assuntos
Antituberculosos/farmacologia , Carbamatos/farmacologia , Compostos Heterocíclicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/farmacologia , Antituberculosos/química , Antituberculosos/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Oximas/química , Oximas/metabolismo , Relação Estrutura-Atividade
6.
Neurology ; 97(7): e673-e683, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34088874

RESUMO

OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNTs treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600-mutant GGNTs and encourages rechallenge in responders. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Azetidinas/farmacologia , Neoplasias Encefálicas/genética , Bases de Dados Factuais , Feminino , Ganglioglioma/tratamento farmacológico , Ganglioglioma/genética , Glioma/genética , Humanos , Imidazóis/farmacologia , Avaliação de Estado de Karnofsky , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Oximas/farmacologia , Piperidinas/farmacologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/farmacologia , Pirimidinonas/farmacologia , Estudos Retrospectivos , Vemurafenib/farmacologia , Quinases raf/antagonistas & inibidores
7.
Molecules ; 26(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064380

RESUMO

The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17ß-hydroxysteroid dehydrogenase type 1 and ß-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and ß-tubulin, which may account for the described effects.


Assuntos
Simulação de Acoplamento Molecular , Oximas/síntese química , Oximas/farmacologia , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Estrona/síntese química , Estrona/química , Estrona/farmacologia , Fluoruracila/farmacologia , Humanos , Concentração Inibidora 50 , Oximas/química
8.
Commun Biol ; 4(1): 573, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990679

RESUMO

Government-sanctioned use of nerve agents (NA) has escalated dramatically in recent years. Oxime reactivators of organophosphate (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) serve as antidotes toward poisoning by OPNAs. The oximes used as therapeutics are quaternary compounds that cannot penetrate the blood-brain barrier (BBB). There remains an urgent need for the development of next generation OPNA therapeutics. We have developed two high-throughput screening (HTS) assays using a fluorogenic NA surrogate, O-ethyl methylphosphonyl O-4-methyl-3-cyano-coumarin (EMP-MeCyC). EMP-MeCyC detoxification and EMP-BChE reactivation screening campaigns of ~155,000 small molecules resulted in the identification of 33 nucleophile candidates, including non-quaternary oximes. Four of the oximes were reactivators of both Sarin- and VX-inhibited BChE and directly detoxified Sarin. One oxime also detoxified VX. The novel reactivators included a non-quaternary pyridine amidoxime, benzamidoxime, benzaldoxime and a piperidyl-ketoxime. The VX-inhibited BChE reactivation reaction rates by these novel molecules were similar to those observed with known bis-quaternary reactivators and faster than mono-quaternary pyridinium oximes. Notably, we discovered the first ketoxime reactivator of OP-ChEs and detoxifier of OPNAs. Preliminary toxicological studies demonstrated that the newly discovered non-quaternary oximes were relatively non-toxic in mice. The discovery of unique non-quaternary oximes opens the door to the design of novel therapeutics and decontamination agents following OPNA exposure.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Agentes Neurotóxicos/toxicidade , Oximas/farmacologia , Animais , Ativação Enzimática , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR
9.
Chem Biodivers ; 18(7): e2100235, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34047003

RESUMO

In search of novel natural product-based bioactive molecules, twenty (ten pairs) novel (Z)-/(E)-anisaldehyde-based oxime ester compounds were designed and synthesized by using anisaldehyde as starting material. Structural characterization of the target compounds was carried out by NMR, FT-IR, ESI-MS, and elemental analysis. Their herbicidal and antifungal activities were preliminarily tested. As a result, at 50 µg/mL, compound (E)-5b exhibited excellent to good inhibition rates of 92.3 %, 79.2 %, and 73.9 %, against Rhizoctonia solani, Fusarium oxysporum f. sp. cucumerinum, and Bipolaris maydis, respectively, better than or comparable to that of the positive control chlorothalonil. In addition, at 100 µg/mL, compounds (E)-5b, (E)-5f, (Z)-5f and (E)-5d exhibited excellent to good inhibition rates of 85.8 %, 82.9 %, 78.6 % and 64.2 %, respectively, against the root-growth of rape (B. campestris), much better than that of the positive control flumioxazin. The bioassay result also showed that the synthesized compounds had obvious differences in antifungal and herbicidal activities between (Z)- and (E)-isomers. Preliminary structure-activity relationship was also discussed by theoretical calculation.


Assuntos
Antifúngicos/farmacologia , Benzaldeídos/farmacologia , Ésteres/farmacologia , Herbicidas/farmacologia , Oximas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Benzaldeídos/síntese química , Benzaldeídos/química , Bipolaris/efeitos dos fármacos , Ésteres/síntese química , Ésteres/química , Fusarium/efeitos dos fármacos , Herbicidas/síntese química , Herbicidas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/síntese química , Oximas/química , Rhizoctonia/efeitos dos fármacos , Relação Estrutura-Atividade
10.
Pest Manag Sci ; 77(9): 3910-3920, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33871901

RESUMO

BACKGROUND: Succinate dehydrogenase inhibitors (SDHIs) play an increasingly important role in controlling plant diseases. However, the similar structures of SDHIs result in rapid development of cross-resistance development and a clear bottleneck of poor activity against oomycetes, therefore the need to seek new SDHI fungicides with novel structures is urgent. RESULTS: Innovative pyrazolyl oxime ethers were designed by replacing amide with oxime ether based on the succinate dehydrogenase (SDH) structure, and 19 pairs of Z- and E-isomers were efficiently prepared for the discovery of SDHI compounds with a novel bridge. Their biological activities against four fungi and two oomycetes were evaluated, and substantial differences were observed between the Z- and E- isomers of the title compounds. Furthermore, most of these compounds exhibited remarkable activities against Rhizoctonia solani with EC50 values of less than 10 mg L-1 in vitro, and bioassay in vivo further confirmed that E-I-6 exhibited good protective efficacy (76.12%) at 200 mg L-1 . In addition, Z-I-12 provided better activity against the oomycetes Pythium aphanidermatum and Phytophthora capsici (EC50  = 1.56 and 0.93 mg L-1 ) than those of boscalid. Moreover, E-I-12 exhibited excellent SDH inhibition (IC50  = 0.21 mg L-1 ) thanks to its good binding ability to the SDH by hydrogen-bonding interactions, π-cation interaction and hydrophobic interactions. CONCLUSION: Novel pyrazolyl oxime ethers have the potential as SDHI compounds for future development, and the strategy of replacing an amide bond with oxime ether may offer an alternative option in SDHI fungicide discovery.


Assuntos
Fungicidas Industriais , Oomicetos , Antifúngicos/farmacologia , Éteres/farmacologia , Fungicidas Industriais/farmacologia , Oximas/farmacologia , Rhizoctonia , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
11.
Future Med Chem ; 13(9): 817-837, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33845591

RESUMO

Nonapoptotic types of regulated cell death have attracted widespread interest since the discovery that certain forms of cell necrosis can be regulated. In particular, research into cell necroptosis has made significant progress in connection with kidney, inflammatory, degenerative and neoplastic diseases. Inhibitors targeting the critical necroptosis-associated proteins RIPK1/3 and MLKL have been in development for more than a decade. Herein the authors compile a list of the known small-molecule inhibitors of these enzymes and representative structures of compounds co-crystallized with these proteins and put forward some thoughts regarding their future development.


Assuntos
Necroptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Necrose/tratamento farmacológico , Oximas/química , Oximas/farmacologia , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Transdução de Sinais
12.
Front Immunol ; 12: 661357, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33828565

RESUMO

In chimeric antigen receptor (CAR)-T cell therapy, the role and mechanism of indoleamine 2, 3 dioxygenase 1 (IDO1) in enhancing antitumor immunity require further study. IDO1 is one of the most important immunosuppressive proteins in esophageal squamous cell carcinoma (ESCC). However, the IDO1 inhibitor, epacadostat, has failed in phase III clinical trials; its limited capacity to inhibit IDO1 expression at tumor sites was regarded as a key reason for clinical failure. In this study, we innovatively loaded the IDO1 inhibitor into hyaluronic acid-modified nanomaterial graphene oxide (HA-GO) and explored its potential efficacy in combination with CAR-T cell therapy. We found that inhibition of the antitumor effect of CAR-T cells in ESCC was dependent on the IDO1 metabolite kynurenine. Kynurenine could suppress CAR-T cell cytokine secretion and cytotoxic activity. Inhibiting IDO1 activity significantly enhanced the antitumor effect of CAR-T cells in vitro and in vivo. Our findings suggested that IDO1 inhibitor-loaded nanosheets could enhance the antitumor effect of CAR-T cells compared with free IDO1 inhibitor. Nanosheet-loading therefore provides a promising approach for improving CAR-T cell therapeutic efficacy in solid tumors.


Assuntos
Imunoterapia Adotiva/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Oximas/farmacologia , Receptores de Antígenos Quiméricos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Nanoestruturas/química , Oximas/química , Receptores de Antígenos Quiméricos/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Sulfonamidas/química , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
13.
Biomed Res Int ; 2021: 5524486, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33880366

RESUMO

Dabrafenib resistance is a significant problem in melanoma, and its underlying molecular mechanism is still unclear. The purpose of this study is to research the molecular mechanism of drug resistance of dabrafenib and to explore the key genes and pathways that mediate drug resistance in melanoma. GSE117666 was downloaded from the Gene Expression Omnibus (GEO) database and 492 melanoma statistics were also downloaded from The Cancer Genome Atlas (TCGA) database. Besides, differentially expressed miRNAs (DEMs) were identified by taking advantage of the R software and GEO2R. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) and FunRich was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to identify potential pathways and functional annotations linked with melanoma chemoresistance. 9 DEMs and 872 mRNAs were selected after filtering. Then, target genes were uploaded to Metascape to construct protein-protein interaction (PPI) network. Also, 6 hub mRNAs were screened after performing the PPI network. Furthermore, a total of 4 out of 9 miRNAs had an obvious association with the survival rate (P < 0.05) and showed a good power of risk prediction model of over survival. The present research may provide a deeper understanding of regulatory genes of dabrafenib resistance in melanoma.


Assuntos
Imidazóis/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , MicroRNAs/genética , Oximas/uso terapêutico , Área Sob a Curva , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Imidazóis/farmacologia , Estimativa de Kaplan-Meier , MicroRNAs/metabolismo , Oximas/farmacologia , Prognóstico , Mapas de Interação de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/genética
14.
Mol Cell ; 81(11): 2290-2302.e7, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33831358

RESUMO

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.


Assuntos
Carcinoma Ductal Pancreático/genética , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Neoplasias Pancreáticas/genética , Células Estreladas do Pâncreas/metabolismo , Evasão Tumoral/efeitos dos fármacos , Aloenxertos , Animais , Antineoplásicos/farmacologia , Carbono/imunologia , Carbono/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Formiatos/imunologia , Formiatos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/genética , Interferon gama/imunologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Oximas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Células Estreladas do Pâncreas/efeitos dos fármacos , Células Estreladas do Pâncreas/imunologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Serina/imunologia , Serina/metabolismo , Serina/farmacologia , Transdução de Sinais , Sulfonamidas/farmacologia , Triptofano/imunologia , Triptofano/metabolismo , Triptofano/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia
15.
Molecules ; 26(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917810

RESUMO

Schwann cell differentiation involves a dynamic interaction of signaling cascades. However, much remains to be elucidated regarding the function of signaling molecules that differ depending on the context in which the molecules are engaged. Here, we identified a small molecule, dabrafenib, which promotes Schwann cell differentiation in vitro and exploited this compound as a pharmacological tool to understand the molecular mechanisms regulating Schwann cell differentiation. The results indicated that dabrafenib inhibited ERK phosphorylation and enhanced ErbB2 autophosphorylation and Akt phosphorylation, and the effects of dabrafenib on ErbB2 and Akt phosphorylation were phenocopied by pharmacological inhibition of the MEK-ERK signaling pathway. However, the small molecule inhibitors of MEK and ERK had no effect on the expression of Oct6 and EGR2, which are key transcription factors that drive Schwann cell differentiation. In addition, pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K) almost completely interfered with dabrafenib-induced Schwann cell differentiation. These results suggest that the ErbB2-PI3K-Akt axis is required for the induction of Schwann cell differentiation by dabrafenib in vitro. Although additional molecules targeted by dabrafenib remain to be identified, our data provides insights into the crosstalk that exists between the MEK-ERK signaling pathway and the PI3K-Akt axis in Schwann cell differentiation.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oximas/farmacologia , Células de Schwann/citologia , Animais , Diferenciação Celular/genética , Imidazóis/química , Oximas/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor ErbB-2/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo
16.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802843

RESUMO

Poisoning with organophosphorus compounds (OPCs) represents an ongoing threat to civilians and rescue personal. We have previously shown that oximes, when administered prophylactically before exposure to the OPC paraoxon, are able to protect from its toxic effects. In the present study, we have assessed to what degree experimental (K-27; K-48; K-53; K-74; K-75) or established oximes (pralidoxime, obidoxime), when given as pretreatment at an equitoxic dosage of 25% of LD01, are able to reduce mortality induced by the OPC azinphos-methyl. Their efficacy was compared with that of pyridostigmine, the only FDA-approved substance for such prophylaxis. Efficacy was quantified in rats by Cox analysis, calculating the relative risk of death (RR), with RR=1 for the reference group given only azinphos-methyl, but no prophylaxis. All tested compounds significantly (p ≤ 0.05) reduced azinphos-methyl-induced mortality. In addition, the efficacy of all tested experimental and established oximes except K-53 was significantly superior to the FDA-approved compound pyridostigmine. Best protection was observed for the oximes K-48 (RR = 0.20), K-27 (RR = 0.23), and obidoxime (RR = 0.21), which were significantly more efficacious than pralidoxime and pyridostigmine. The second-best group of prophylactic compounds consisted of K-74 (RR = 0.26), K-75 (RR = 0.35) and pralidoxime (RR = 0.37), which were significantly more efficacious than pyridostigmine. Pretreatment with K-53 (RR = 0.37) and pyridostigmine (RR = 0.52) was the least efficacious. Our present data, together with previous results on other OPCs, indicate that the experimental oximes K-27 and K-48 are very promising pretreatment compounds. When penetration into the brain is undesirable, obidoxime is the most efficacious prophylactic agent already approved for clinical use.


Assuntos
Azinfos-Metil/toxicidade , Oximas/farmacologia , Animais , Azinfos-Metil/química , Inibidores da Colinesterase/farmacologia , Concentração Inibidora 50 , Peso Molecular , Compostos Organofosforados/química , Compostos Organofosforados/toxicidade , Praguicidas/química , Praguicidas/toxicidade , Modelos de Riscos Proporcionais , Ratos Wistar , Risco , Análise de Sobrevida
17.
J Biochem Mol Toxicol ; 35(6): 1-10, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33682265

RESUMO

Past assassinations and terrorist attacks demonstrate the need for a more effective antidote against nerve agents and other organophosphates (OP) that cause brain damage through inhibition of acetylcholinesterase (AChE). Our lab has invented a platform of phenoxyalkyl pyridinium oximes (US patent 9,277,937) that demonstrate the ability to cross the blood-brain barrier in in vivo rat tests with a sarin surrogate nitrophenyl isopropyl methylphosphonate (NIMP) and provide evidence of brain penetration by reducing cessation time of seizure-like behaviors, accumulation of glial fibrillary acidic protein (GFAP), and hippocampal neuropathology, as opposed to the currently approved oxime, 2-pyridine aldoxime methyl chloride (2-PAM). Using two of the novel oximes (Oximes 1 and 20), this project examined whether gene expression changes might help explain this protection. Expression changes in the piriform cortex were examined using polymerase chain reaction arrays for inflammatory cytokines and receptors. The hippocampus was examined via quantitative polymerase chain reaction for the expression of immediate-early genes involved in brain repair (Bdnf), increasing neurotoxicity (Fos), and apoptosis control (Jdp2, Bcl2l1, Bcl2l11). In the piriform cortex, NIMP significantly stimulated expression for the macrophage inflammatory proteins CCL4, IL-1A, and IL-1B. Oxime 20 by itself elicited the most changes. When it was given therapeutically post-NIMP, the largest change occurred: a 310-fold repression of the inflammatory cytokine, CCL12. In the hippocampus, NIMP increased the expression of the neurotoxicity marker Fos and decreased the expression of neuroprotective Bdnf and antiapoptotic Bcl2l1. Compared with 2-PAM, Oxime 20 stimulated Bcl2l1 expression more and returned expression closer to the vehicle control values.


Assuntos
Acetilcolinesterase , Encéfalo/metabolismo , Reativadores da Colinesterase , Regulação da Expressão Gênica/efeitos dos fármacos , Oximas , Sarina/toxicidade , Acetilcolinesterase/metabolismo , Animais , Encéfalo/patologia , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacocinética , Reativadores da Colinesterase/farmacologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Masculino , Oximas/química , Oximas/farmacocinética , Oximas/farmacologia , Ratos , Ratos Sprague-Dawley
18.
Eur J Med Chem ; 217: 113340, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33725630

RESUMO

A novel class of 7-thiazoxime quinolones was developed as potential antimicrobial agents for the sake of bypassing resistance of quinolones. Biological assays revealed that some constructed 7-thiazoxime quinolones possessed effective antibacterial efficiency. Methyl acetate oxime derivative 6l exhibited 32-fold more active than ciprofloxacin against MRSA, which also possessed rapidly bactericidal ability and low toxicity towards mammalian cells. The combination use of 7-thiazoxime quinolone 6l and ciprofloxacin was able to improve antibacterial potency and effectively alleviate bacterial resistance. The preliminarily mechanism exploration revealed that compound 6l could destroy the cell membrane and insert into MRSA DNA to bind with DNA gyrase, then decrease the expression of gyrB and femB genes. The above results strongly suggested that methyl acetate oxime derivative 6l held a promise for combating MRSA infection.


Assuntos
Antibacterianos/farmacologia , DNA Bacteriano/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oximas/farmacologia , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Sítios de Ligação/efeitos dos fármacos , DNA Bacteriano/genética , Relação Dose-Resposta a Droga , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/síntese química , Oximas/química , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 40: 127928, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705899

RESUMO

Four new aminothiazole-oximepiperidone cephalosporins (10a-10d) were synthesized, with their in vitro antibacterial activities against hospital isolated Gram-negative bacteria assessed. The results showed that compounds 10a-10d effectively inhibit a variety of Gram-negative bacteria. Compound 10a was the most potent compound, with comparable activity as ceftazidime. The combination of compound 10a and Avibactam was very active against almost all bacteria tested, which including multidrug resistant K. pneumoniae and A. baumannii. Compared to Avycaz, this combination is more potent against ESBL producing K. pneumoniae. Thus, the combination of 10a and Avibactam is of interest for further studies.


Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Oximas/farmacologia , Piperidonas/farmacologia , Tiazóis/farmacologia , Antibacterianos/síntese química , Compostos Azabicíclicos/farmacologia , Cefalosporinas/síntese química , Combinação de Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Oximas/síntese química , Piperidonas/síntese química , Tiazóis/síntese química
20.
Bioorg Med Chem Lett ; 40: 127963, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33741464

RESUMO

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are rate-limiting enzymes in the kynurenine pathway (KP) of l-tryptophan (l-Trp) metabolism and are becoming key drug targets in the combination therapy of checkpoint inhibitors in immunoncology. To discover a selective and potent IDO1 inhibitor, a structure-activity relationship (SAR) study of N-hydroxybenzofuran-5-carboximidamide as a novel scaffold was investigated in a systematic manner. Among the synthesized compounds, the N-3-bromophenyl derivative 19 showed the most potent inhibition, with an IC50 value of 0.44 µM for the enzyme and 1.1 µM in HeLa cells. The molecular modeling of 19 with the X-ray crystal structure of IDO1 indicated that dipole-ionic interactions with heme iron, halogen bonding with Cys129 and the two hydrophobic interactions were important for the high potency of 19.


Assuntos
Amidinas/farmacologia , Benzofuranos/farmacologia , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Oximas/farmacologia , Amidinas/síntese química , Amidinas/metabolismo , Benzofuranos/síntese química , Benzofuranos/metabolismo , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/síntese química , Oximas/metabolismo , Ligação Proteica , Eletricidade Estática , Relação Estrutura-Atividade
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