RESUMO
Twenty-four 1,2-diarylbenzimidazole derivatives were designed, synthesized and biologically evaluated. It turned out that most of them were potential anticancer drugs. Among them, compound c24 showed the highest anti-tumor activity (GI50â¯=â¯0.71-2.41⯵M against HeLa, HepG2, A549 and MCF-7 cells), and low toxicity to normal cells (CC50â¯>â¯100⯵M against L02 cells). In the microtubule binding assay, c24 showed the most potent inhibition of microtubule polymerization (IC50â¯=â¯8.47⯵M). The binding ability of compound c24 to tubulin crystal was verified by molecular docking simulation experiment. Further studies on HepG2 and HeLa cells showed that compound c24 could cause mitotic arrest of tumor cells to G2/M phase then inducing apoptosis. To sum up, compound c24 is a promising microtubule assembly inhibitor.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Simulação de Acoplamento Molecular , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
Long-term peritoneal dialysis is accompanied by functional and histopathological alterations in the peritoneal membrane. In the long process of peritoneal dialysis, high-glucose peritoneal dialysis solution (HGPDS) will aggravate the peritoneal fibrosis, leading to decreased effectiveness of peritoneal dialysis and ultrafiltration failure. In this study, we found that the coincidence of elevated TGF-ß1 expression, autophagy, apoptosis and fibrosis in peritoneal membrane from patients with peritoneal dialysis. The peritoneal membranes from patients were performed with immunocytochemistry and transmission electron microscopy. Human peritoneal mesothelial cells were treated with 1.5%, 2.5% and 4.25% HGPDS for 24 hrs; Human peritoneal mesothelial cells pre-treated with TGF-ß1 (10 ng/ml) or transfected with siRNA Beclin1 were treated with 4.25% HGPDS or vehicle for 24 hrs. We further detected the production of TGF-ß1, activation of TGF-ß1/Smad2/3 signalling, induction of autophagy, EMT, fibrosis and apoptosis. We also explored whether autophagy inhibition by siRNA targeting Beclin 1 reduces EMT, fibrosis and apoptosis in human peritoneal mesothelial cells. HGPDS increased TGF-ß1 production, activated TGF-ß1/Smad2/3 signalling and induced autophagy, fibrosis and apoptosis hallmarks in human peritoneal mesothelial cells; HGPDS-induced Beclin 1-dependent autophagy in human peritoneal mesothelial cells; Autophagy inhibition by siRNA Beclin 1 reduced EMT, fibrosis and apoptosis in human peritoneal mesothelial cells. Taken all together, these studies are expected to open a new avenue in the understanding of peritoneal fibrosis, which may guide us to explore the compounds targeting autophagy and achieve the therapeutic improvement of PD.
Assuntos
Apoptose , Autofagia , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/patologia , Peritônio/patologia , Adulto , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Cateterismo , Soluções para Diálise/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Epitélio/ultraestrutura , Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Peritônio/efeitos dos fármacos , Peritônio/ultraestrutura , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Helicobacter pylori infection is the main cause of chronic gastritis, peptic ulcer, and gastric cancer. Tip-α is a newly identified carcinogenic factor present in H. pylori. TRAF3 can activate NF-κB by both canonical and noncanonical signaling pathways. In this study, we found that the expression of TRAF3 and NF-κB was upregulated, while microRNA-3178 (miR-3178) was decreased in H. pylori-positive gastric tissues but not in H. pylori-negative tissues. MATERIALS AND METHODS: GES-1 cells were incubated with 12.5 µg/mL recombinant Tip-α (rTip-α) in RPMI1640 for 2 hours. After another 24 hours, the supernatant medium was designed as inflammatory-conditioned medium (ICM) and that from the untreated control cells was designed as untreated control medium. The release of proinflammatory cytokines from GES-1 cells and proliferation of gastric cancer cells was determined by ELISA and CCK-8 kits. Cells were transfected with the mimic, inhibitor, negative control of miR-3178, or TRAF3 siRNA control siRNA. The medium was then replaced with RPMI1640, 12.5 µg/mL rTip-α, and collected, and the total cellular RNA and protein were extracted for the following detection. RESULTS: MiR-3178 mimic prevented the increasement of TRAF3 and hence decreased activation of NF-κB signals, whereas miR-3178 inhibitor could not, in GES-1 cells with Tip-α treatment. The condition medium from miR-3178 mimic transfected GES-1 cells could inhibit proliferation and induce apoptosis of inflammation-related gastric cancer cells SGC7901 and MGC803 by decreasing the production of inflammatory cytokines TNF-α and IL-6, which were secreted by GES-1 cells. CONCLUSIONS: Taken all together, Tip-α might activate NF-κB to promote inflammation and carcinogenesis by inhibiting miR-3178 expression, which directly targeting TRAF3, during H. pylori infection in gastric mucosal epithelial cells.
Assuntos
Toxinas Bacterianas/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Helicobacter pylori/patogenicidade , MicroRNAs/metabolismo , Fator 3 Associado a Receptor de TNF/metabolismo , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/imunologia , Células Epiteliais/fisiologia , HumanosRESUMO
UNLABELLED: The success of future clinical trials with oncolytic viruses depends on the identification and the control of mechanisms that modulate their therapeutic efficacy. In particular, little is known about the role of autophagy in infection by attenuated measles virus of the Edmonston strain (MV-Edm). We investigated the interaction between autophagy, innate immune response, and oncolytic activity of MV-Edm, since the antiviral immune response is a known factor limiting virotherapies. We report that MV-Edm exploits selective autophagy to mitigate the innate immune response mediated by DDX58/RIG-I like receptors (RLRs) in non-small cell lung cancer (NSCLC) cells. Both RNA interference (RNAi) and overexpression approaches demonstrate that autophagy enhances viral replication and inhibits the production of type I interferons regulated by RLRs. We show that MV-Edm unexpectedly triggers SQSTM1/p62-mediated mitophagy, resulting in decreased mitochondrion-tethered mitochondrial antiviral signaling protein (MAVS) and subsequently weakening the innate immune response. These results unveil a novel infectious strategy based on the usurpation of mitophagy leading to mitigation of the innate immune response. This finding provides a rationale to modulate autophagy in oncolytic virotherapy. IMPORTANCE: In vitro studies, preclinical experiments in vivo, and clinical trials with humans all indicate that oncolytic viruses hold promise for cancer therapy. Measles virus of the Edmonston strain (MV-Edm), which is an attenuated virus derived from the common wild-type measles virus, is paradigmatic for therapeutic oncolytic viruses. MV-Edm replicates preferentially in and kills cancer cells. The efficiency of MV-Edm is limited by the immune response of the host against viruses. In our study, we revealed that MV-Edm usurps a homeostatic mechanism of intracellular degradation of mitochondria, coined mitophagy, to attenuate the innate immune response in cancer cells. This strategy might provide a replicative advantage for the virus against the development of antiviral immune responses by the host. These findings are important since they may not only indicate that inducers of autophagy could enhance the efficacy of oncolytic therapies but also provide clues for antiviral therapy by targeting SQSTM1/p62-mediated mitophagy.
Assuntos
RNA Helicases DEAD-box/metabolismo , Vírus do Sarampo/fisiologia , Mitofagia , Vírus Oncolíticos/fisiologia , Transdução de Sinais , Replicação Viral , Linhagem Celular Tumoral , Proteína DEAD-box 58 , Humanos , Imunidade Inata , Vírus do Sarampo/imunologia , Receptores ImunológicosRESUMO
Glucagon-like peptide-1 (GLP-1) plays an important role in the regulation of postprandial insulin release. Here, we used the split DnaB mini-intein system to produce recombinant human GLP-1/7-36 (rhGLP-1) in Escherichia coli. The C-terminal domain of DnaB mini-intein (IntC) was genetically fused at the N-terminus of rhGLP-1 to produce IntC-GLP-1. IntC-GLP-1 and N-terminal domain of DnaB mini-intein (IntN) protein were prepared in a denatured buffer of pH 8.0. IntC-GLP-1 was diluted 1:8 into the phosphate buffer of pH 6.6. IntN was added into the diluted solution of IntC-GLP-1 at the molar ratio of 1:2. Then, rhGLP-1 was released from IntC-GLP-1 via inducible C-terminal peptide-bond cleavage by shifting pH from 8.0 to 6.6 at 25 °C for 24-H incubation. Then, the supernatant was applied to a Ni-Sepharose column, and the pass through fraction was collected. About 5.34 mg of rhGLP-1 with the purity of 97% was obtained from 1 L of culture medium. Mass spectrometry showed the molecular weight of 3,300.45 Da, which was equal to the theoretical value of GLP-1/7-36. The glucose-lowering activity of rhGLP-1 was confirmed by the glucose tolerance test in mice. In conclusion, the reported method was an efficient strategy to produce rhGLP-1 without using enzyme or chemical reagents, which could also be used for other similar peptides.
Assuntos
Clonagem Molecular/métodos , DnaB Helicases/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Inteínas/genética , Proteínas Recombinantes de Fusão/metabolismo , Escherichia coli/genética , Peptídeo 1 Semelhante ao Glucagon/química , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/isolamento & purificação , Humanos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificaçãoRESUMO
A series of metronidazolethiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, (1)H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5 e exhibited the most potent inhibitory activity against E. coli FabH with IC50 of 4.9 lM. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5 a, 5 b, 5 d, 5 e, 5 g and 5 i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Desenho de Fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Metronidazol/química , Tiazóis/química , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase , Acetiltransferases/antagonistas & inibidores , Acetiltransferases/metabolismo , Antibacterianos/metabolismo , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Ácido Graxo Sintase Tipo II/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Terciária de ProteínaRESUMO
A series of metronidazole-thiazole derivatives has been designed, synthesized and evaluated as potential antibacterial inhibitors. All the synthesized compounds were determined by elemental analysis, 1H NMR and MS. They were also tested for antibacterial activity against Escherichia coli, Bacillus thuringiensis, Bacillus subtilis and Pseudomonas aeruginosa as well as for the inhibition to FabH. The results showed that compound 5e exhibited the most potent inhibitory activity against E. coli FabH with IC50 of 4.9µM. Molecular modeling simulation studies were performed in order to predict the biological activity of proposed compounds. Toxicity assay of compounds 5a, 5b, 5d, 5e, 5g and 5i showed that they were noncytotoxic against human macrophage. The results revealed that these compounds offered remarkable viability.
RESUMO
A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11 µM and Hela with IC50 value of 2.54 µM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50=0.45 µM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Dioxanos/química , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Simulação de Acoplamento Molecular , Nitroimidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Células HeLa , Humanos , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
A series of 1,3,4-thiadiazol-2-amide derivatives (6a-w) were designed and synthesized as potential inhibitors of tubulin polymerization and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 6f exhibited the most potent anticancer activity against A549, MCF-7 and HepG2 cancer cell lines with IC50 values of 0.03 µM, 0.06 µM and 0.05 µM, respectively. Compound 6f also exhibited significant tubulin polymerization inhibitory activity (IC50=1.73 µM), which was superior to the positive control. The obtained results, along with a 3D-QSAR study and molecular docking that were used for investigating the probable binding mode, could provide an important basis for further optimization of compound 6f as a novel anticancer agent.
Assuntos
Amidas/química , Amidas/farmacologia , Antineoplásicos/síntese química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Amidas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Células MCF-7 , Conformação Molecular , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Moduladores de Tubulina/químicaRESUMO
A murine monoclonal antibody (mAb) 3C7 against integrin αIIbß3 was previously obtained as a potential antithrombotic agent in our laboratory. The epitope of 3C7 is a specific conformation of the αIIbß3 complex, but not either of the two subunits, which makes it different from abciximab, a supplementary antibody drug used in percutaneous coronary intervention which has a cross-reaction with other integrins sharing the ß3 subunit. To reduce the human anti-mouse antibody reactions of 3C7, the variable regions of this antibody were cloned and fused with the constant counterparts of human IgG1. Two vectors of light and heavy chains were constructed and co-transfected into CHO-dhfr(-) cells. The chimeric antibody c3C7 was purified and the properties of c3C7 were compared with 3C7. Identical to its parent antibody 3C7, c3C7 binds to the αIIbß3 complex, but not to either of the subunits. The K(d) value of c3C7 was in the same order of magnitude as 3C7 (1.570 ± 0.326 vs 0.780 ± 0.182 nmol/L). Human platelet aggregation induced by adenosine diphosphate was effectively inhibited by c3C7 in a dose-dependent manner. In conclusion, after the modification, c3C7 retained the properties of its parent mAb with no loss of its biological activity. Therefore, c3C7 has the potential to become a novel agent for the treatment of thrombosis.
Assuntos
Anticorpos/genética , Anticorpos/imunologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Animais , Anticorpos/isolamento & purificação , Células CHO , Cricetinae , Cricetulus , Humanos , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Imunoglobulina G/isolamento & purificação , Camundongos , Agregação Plaquetária/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND AND PURPOSE: Panax ginseng is widely applied in the adjuvant treatment of cardiometabolic diseases in clinical practice without clear mechanisms. This study aims to clearly define the efficacy and underlying mechanism of P. ginseng and its active components in protecting against atherosclerosis. EXPERIMENTAL APPROACH: The anti-atherogenic efficacy of total ginseng saponin extract (TGS) and its components was evaluated on Ldlr-/- mice. Gut microbial structure was analysed by 16S rRNA sequencing and PCR. Bile acid profiles were revealed using targeted metabolomics with LC-MS/MS analysis. The contribution of gut microbiota to atherosclerosis was assessed by co-housing experiments. KEY RESULTS: Ginsenoside Rb1, representing protopanaxadiol (PPD)-type saponins, increased intestinal Lactobacillus abundance, resulting in enhanced bile salt hydrolase (BSH) activity to promote intestinal conjugated bile acid hydrolysis and excretion, followed by suppression of enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signal, and thereby increased cholesterol 7α-hydroxylase (CYP7A1) transcriptional expression and facilitated metabolic elimination of cholesterol. Synergistically, protopanaxatriol (PPT)-type saponins, represented by ginsenoside Rg1, protected against atherogenesis-triggered gut leak and metabolic endotoxaemia. Ginsenoside Rg1 directly induced mucin production to nutritionally maintain Akkermansia muciniphila, which reciprocally inhibited gut permeation. Rb1/Rg1 combination, rather than a single compound, can largely mimic the holistic efficacy of TGS in protecting Ldlr-/- mice from atherogenesis. CONCLUSION AND IMPLICATIONS: Our study provides strong evidence supporting TGS and ginsenoside Rb1/Rg1 combinations as effective therapies against atherogenesis, via targeting different signal nodes by different components and may provide some elucidation of the holistic mode of herbal medicines.
Assuntos
Aterosclerose , Microbioma Gastrointestinal , Ginsenosídeos , Homeostase , Camundongos Knockout , Panax , Animais , Ginsenosídeos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Masculino , Camundongos , Panax/química , Camundongos Endogâmicos C57BL , Ácidos e Sais Biliares/metabolismo , Receptores de LDL/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Amidoidrolases/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismoRESUMO
1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC50 values of 5.68 µg/ml and 10.21 µg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP-PCR-ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC50 values of 1.2±0.3 µM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Oxidiazóis/química , Oxidiazóis/farmacologia , Triazóis/química , Triazóis/farmacologia , Antineoplásicos/síntese química , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Células HT29 , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Oxidiazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Triazóis/síntese químicaRESUMO
Human serum albumin (HSA) is a biological macromolecule with important physiological functions; abnormal HSA levels are associated with coronary heart disease, multiple myeloma, diabetes, nephropathy, neurometabolic disorders, liver cirrhosis and other diseases. Therefore, accurate and quantitative detection of HAS have extremely important research and application value in biological science, molecular biology, clinical medicine and other fields. As for the detection method of HSA, dye-binding method and immune method are the first to be used, and have been applied in clinical detection. In recent years, many new detection technologies have emerged, such as fluorescent probe detection method, nano-materials for HSA detection, biosensor and so on. Although there are many methods developed recently to detect HSA, comprehensive reviews for HSA detection methods are still rare. Thus, writing this review to fill in the blank is in need. In order to highlight the recent progress in the field of HSA detection, in this review, the methods used to detect HSA are summarized and sorted, the advantages and disadvantages of these detection methods are also listed, then the research progress of small molecular fluorescence probe method is emphatically introduced in this paper. Then, we briefly discussed the challenges and future development directions in this field.
Assuntos
Técnicas Biossensoriais , Albumina Sérica Humana , Corantes Fluorescentes , Humanos , Espectrometria de FluorescênciaRESUMO
BACKGROUND: In the past few decades, with the abuse of antibiotics, bacterial resistance has enhanced constantly. More and more super species of bacteria, which are seriously threatening human health, have been discovered. Developing novel antibacterial agents to overcome the drug-resistance is an urgent duty. We all know that blocking the information-transfer of bacterial DNA and RNA is one of the effective ways to inhibit bacterial growth. Therefore, as the indispensable enzyme for DNA replication and transcription, DNA gyrase is one of the important targets for bacterial inhibitors. Accordingly, many inhibitors of DNA gyrase have also been developed. METHODS: In this review, to highlight the recent progress in DNA gyrase inhibitors, the study in this field over the past three years (2017-2019) was summarized and organized based on their backbones or core moieties. Both of the subunits of DNA gyrase were taken into consideration. RESULTS: These DNA gyrase inhibitors have been classified based on their backbones or core moieties. After the comparison of the divided 14 categories, we could achieve some clues for future modification. In particular, we found that benzodiazepines and naphthalene heterocycles were the most common structures in the drug design. On the other hand, isopropyl and cyclopropyl have also been used in drug design, which provides more inspiration for the investigations. Except for GSK2140944, which has entered the phase III clinical trial stage, other compounds here were not fully promulgated with their optimal pharmacokinetic activity. CONCLUSION: We briefly summed up the current situation and future challenges on this topic. Through the discussion of the design strategies and drug effect, we hope that this review can provide a focused direction for future researches.
Assuntos
DNA Girase , Inibidores da Topoisomerase II , Antibacterianos/farmacologia , Bactérias , DNA Bacteriano , Humanos , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II/farmacologiaRESUMO
Introduction: RAF kinase inhibitors block and regulate RAS/RAF/MEK/ERK signaling, which is a key to tumor treatment. At present, although RAF kinase inhibitors have good efficacy, there are few such drugs with low toxicity, and thus, it is urgent to find novel RAF kinase inhibitors associated with higher activity and fewer adverse reactions. This review highlights the anti-tumor effects of several published RAF kinase inhibitors and might be helpful in providing new ideas for the development of novel drug candidates in the future. Areas covered: This article covers the pertinent literature published on RAF kinase inhibitors from 2010 to 2018, as well as the potential use of these compounds as therapeutics for cancer. Expert opinion: To date, many RAF kinase inhibitors with different structures have been studied, many of which have prominent inhibitory activities toward RAF kinase. Further, the specificity of these drugs offers hope for the targeted therapy of tumors. Although RAF kinase inhibition has achieved promising results for the treatment of many cancers, overcoming limitations associated with drug resistance and safety comprises a new direction for the optimization and improvement of RAF kinase inhibitors.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Quinases raf/antagonistas & inibidores , Animais , Desenvolvimento de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Patentes como Assunto , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases raf/metabolismoRESUMO
In current work, a class of novel 4,5-dihydro-1H-pyrazole-1-carboxylate derivatives (E01-E28) were designed, synthesized and evaluated. Among them, the most potent compound E24 exhibited comparable activity against a panel of cancer cells (GI50 ranging 0.05-0.98⯵M) and tubulin polymerization inhibition (IC50â¯=â¯1.49⯵M) with reference drug CA-4(P) (GI50 ranging 0.019-0.32⯵M, IC50â¯=â¯2.18⯵M). The following assays indicated that compound E24 disturbed the dynamics of tubulin catastrophe and rescue, which triggered G2/M arrest, leading to ROS accumulation, cleavage of PARP and apoptosis. Molecular dynamics simulation validated that compound E24 could tightly bind into tubulin heterodimers with ß Lys 254 and ß Cys 241 of tubulin in the docking pose. Metabolic stability and pharmacokinetics parameters were also determined. The half time (t1/2) displayed species differences in three microsomes. The plasma elimination half-life (t1/2), peak plasma concentration (Cmax), mean retention time (MRT), the area under the curve (AUC0-∞) and distribution volume (Vz) of E24 after intravenous administration were 0.90 ± 0.22 h, 594.50 ± 97.23 ng/mL, 1.09 ± 0.22 h, 413.67 ± 105.64 ng/mL*h and 5.03 ± 1.82 L/kg, respectively. In HeLa-xenografts, compound E24 exhibited obvious antitumor efficacy via the suppression of tumor growth without weight loss of body or organ. In brief, compound E24 might be a hopeful candidate with excellent properties for oncotherapy as tubulin polymerization inhibitor.
Assuntos
Antineoplásicos/síntese química , Polimerização/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Xenoenxertos , Humanos , Camundongos , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese químicaRESUMO
INTRODUCTION: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes at sites of cell adhesion to the extracellular matrix (ECM) and mediates signalling events downstream of integrin engagement of the ECM. FAK is known to regulate cell survival, proliferation and migration. AREAS COVERED: FAK expression has also been shown to be up-regulated in many cancer types. Previous study also indicates that FAK-mediated signaling and functions are intrinsically involved in the progression of tumor aggressiveness, suggesting that FAK is a promising target for anticancer therapies. Small molecule FAK inhibitors have been developed and are being tested in clinical phase trials. EXPERT OPINION: These inhibitors have demonstrated to be effective by inducing tumor cell apoptosis in addition to reducing metastasis and angiogenesis. In this review, we give updates on the design, synthesis and structure-activity relationship analysis of small molecule FAK inhibitors discovered from 2015 until now. We also review the FAK inhibitors that are in clinical development and highlight the future prospects.
Assuntos
Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Progressão da Doença , Desenho de Fármacos , Proteína-Tirosina Quinases de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Patentes como Assunto , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Oncolytic measles virus (OMV) is a promising antitumor agent. However, the presence of anti-measles neutralizing antibodies (NAbs) against the hemagglutinin (H) protein of OMV is a major barrier to the therapeutic application of OMV in clinical practice. In order to overcome this challenge, specific types of cells have been used as carriers for OMV. Differential loading strategies appear to result in different therapeutic outcomes; despite this, only few studies have reported practical ex vivo loading strategies required for effective treatment. To this end, we systematically evaluated the antitumor efficacy of OMV using different loading strategies; this involved varying the in vitro loading duration and loading dose of OMV. We found that improved oncolysis of carrier cells was achieved by a prolonged loading duration in the absence of NAbs. However, the enhanced oncolytic effect was abrogated in the presence of NAbs. Further, we found that the expression of H protein on the surface of carrier cells was predominantly determined by the loading duration rather than the loading dose. Finally, we showed that NAbs blocked viral transfer by targeting H protein prior to the occurrence of cell-to-cell interactions. Our results provide comprehensive information on the determinants of an effective loading strategy for carrier cell-based virotherapy; these results may be useful for guiding the application of OMV as an antitumor agent in clinical practice.
Assuntos
Células Endoteliais/virologia , Vírus do Sarampo/fisiologia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Células A549 , Animais , Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacologia , Chlorocebus aethiops , Humanos , Soros Imunes/farmacologia , Células Jurkat , Células VeroRESUMO
There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8+NKG2D+ cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8+NKG2D+ cells, mediated by at least three distinct mechanisms. First, MV-Edm infection compelled HCC cells to express the specific NKG2D ligands MICA/B, which may contribute to the activation of CD8+NKG2D+ cells. Second, MV-Edm-infected HCC cells stimulated CD8+NKG2D+ cells to express high level of FasL resulting in enhanced induction of apoptosis. Third, intratumoural administration of MV-Edm enhanced infiltration of intravenously injected CD8+NKG2D+ cells. Moreover, we found that MV-Edm and adoptive CD8+NKG2D+ cells, either administered alone or combined, upregulated the immune suppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in HCC. Elimination of IDO1 by fludarabine enhanced antitumour responses. Taken together, our data provide a novel and clinically relevant strategy for treatment of HCC.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Vírus do Sarampo/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Vírus Oncolíticos/imunologia , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Efeito Citopatogênico Viral , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Vírus do Sarampo/genética , Camundongos , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Autophagy is a tightly regulated process activated in response to metabolic stress and other microenvironmental changes. Astrocyte elevated gene 1 (AEG-1) reportedly induces protective autophagy. Our results indicate that AEG-1 also enhances the susceptibility of malignant glioma cells to TGF-ß1-triggered epithelial-mesenchymal transition (EMT) through induction of autophagy. TGF-ß1 induced autophagy and activated AEG-1 via Smad2/3 phosphorylation in malignant glioma cells. Also increased was oncogene cyclin D1 and EMT markers, which promoted tumor progression. Inhibition of autophagy using siRNA-BECN1 and siRNA-AEG-1 suppressed EMT. In tumor samples from patients with malignant glioma, immunohistochemical assays showed that expression levels of TGF-ß1, AEG-1, and markers of autophagy and EMT, all gradually increase with glioblastoma progression. In vivo siRNA-AEG-1 administration to rats implanted with C6 glioma cells inhibited tumor growth and increased the incidence of apoptosis among tumor cells. These findings shed light on the mechanisms underlying the invasiveness and progression of malignant gliomas.