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1.
Anticancer Res ; 41(10): 4753-4759, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593424

RESUMO

BACKGROUND/AIM: De-differentiation is a key step for the progression of cancer cells. This study investigated the anti-tumor effect of kartogenin (KGN), which has the ability to differentiate cells, on prostate cancer (PC) cells. MATERIALS AND METHODS: The effects of KGN on androgen receptor (AR) nuclear localization, prostate-specific antigen (PSA) expression, and Smad2 activation as well as the growth of PC cell lines (LNCaP, 22Rv1 and PC-3) were analyzed. RESULTS: KGN significantly inhibited growth of AR-expressing LNCaP and 22Rv1 cells but not of AR-lacking PC-3 cells. KGN decreased AR nuclear localization and PSA expression, but did not enhance the anti-tumor effect of bicalutamide in LNCaP cells. KGN activated Smad2 both in the absence and presence of TGF-ß1. KGN also inhibited growth of docetaxel-resistant PC cells, 22Rv1DR, and re-sensitized them to the agent. CONCLUSION: KGN has a potential as a novel therapeutic for PC patients after treatment failure.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Núcleo Celular/metabolismo , Ácidos Ftálicos/farmacologia , Receptores Androgênicos/metabolismo , Proteína Smad2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Fator de Crescimento Transformador beta1/farmacologia
2.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575841

RESUMO

Two novel bioisosteres of cabozantinib, 3 and 4, were designed and synthesized. The benzene ring in the center of the cabozantinib structure was replaced by trimethylpyridine (3) and pyridine (4), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchymal-epithelial transition factor (c-Met) inhibitory activities at 1 µM concentration (4% inhibition of 3 vs. 94% inhibition of 4). The IC50 value of compound 4 was 4.9 nM, similar to that of cabozantinib (5.4 nM). A ligand-based docking study suggested that 4 includes the preferred conformation for the binding to c-Met in the conformational ensemble, but 3 does not. The anti-proliferative activity of compound 4 against hepatocellular carcinoma (Hep3B and Huh7) and non-small-cell lung cancer (A549 and H1299) cell lines was better than that of cabozantinib, whereas 3 did not show a significant anti-proliferative activity. Moreover, the tumor selectivity of compound 4 toward hepatocellular carcinoma cell lines was higher than that of cabozantinib. In the xenograft chick tumor model, compound 4 inhibited Hep3B tumor growth to a much greater extent than cabozantinib. The present study suggests that compound 4 may be a good therapeutic candidate against hepatocellular carcinoma.


Assuntos
Anilidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridinas/farmacologia , Anilidas/síntese química , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Piridinas/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Sci Rep ; 11(1): 15887, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354111

RESUMO

The androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic efficacy remains unclear, due to the lack of detailed structural information of the AR bound to the antagonists. We have performed accelerated molecular dynamics (aMD) simulations of LBDs bound to a set of ligands including a natural substrate (dihydrotestosterone), an agonist (RU59063) and three antagonists (bicalutamide, enzalutamide and apalutamide) as well as in the absence of ligand (apo). We show that the binding of AR antagonists at the substrate binding pocket alter the dynamic fluctuations of H12, thereby disrupting the structural integrity of the agonistic conformation of AR. Two antagonists, enzalutamide and apalutamide, induce considerable structural changes to the agonist conformation of LBD, when bound close to H12 of AR LBD. When the antagonists bind to the pocket with different orientations having close contact with H11, no significant conformational changes were observed, suggesting the AR remains in the functionally activated (agonistic) state. The simulations on a drug resistance mutant F876L bound to enzalutamide demonstrated that the mutation stabilizes the agonistic conformation of AR LBD, which compromises the efficacy of the antagonists. Principal component analysis (PCA) of the structural fluctuations shows that the binding of enzalutamide and apalutamide induce conformational fluctuations in the AR, which are markedly different from those caused by the agonist as well as another antagonist, bicalutamide. These fluctuations could only be observed with the use of aMD.


Assuntos
Antagonistas de Receptores de Andrógenos/química , Androgênios/química , Receptores Androgênicos/ultraestrutura , Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios/metabolismo , Anilidas/farmacologia , Benzamidas/farmacologia , Sítios de Ligação , Di-Hidrotestosterona/farmacologia , Humanos , Imidazóis/farmacologia , Ligantes , Conformação Molecular , Simulação de Dinâmica Molecular , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Análise de Componente Principal , Ligação Proteica , Conformação Proteica , Receptores Androgênicos/metabolismo , Receptores Androgênicos/fisiologia , Tioidantoínas/farmacologia , Compostos de Tosil/farmacologia
4.
Exp Cell Res ; 406(1): 112736, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273404

RESUMO

Electric field (EF) directed cell migration (electrotaxis) is known to occur in glioblastoma multiforme (GBM) and neural stem cells, with key signalling pathways frequently dysregulated in GBM. One such pathway is EGFR/PI3K/Akt, which is down-regulated by peroxisome proliferator activated receptor gamma (PPARγ) agonists. We investigated the effect of electric fields on primary differentiated and glioma stem cell (GSCs) migration, finding opposing preferences for anodal and cathodal migration, respectively. We next sought to determine whether chemically disrupting Akt through PTEN upregulation with the PPARγ agonist, pioglitazone, would modulate electrotaxis of these cells. We found that directed cell migration was significantly inhibited with the addition of pioglitazone in both differentiated GBM and GSCs subtypes. Western blot analysis did not demonstrate any change in PPARγ expression with and without exposure to EF. In summary we demonstrate opposing EF responses in primary GBM differentiated cells and GSCs can be inhibited chemically by pioglitazone, implicating GBM EF modulation as a potential target in preventing tumour recurrence.


Assuntos
Movimento Celular/genética , Células-Tronco Neoplásicas/metabolismo , Neuroglia/metabolismo , PPAR gama/genética , Resposta Táctica , Anilidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Eletricidade , Eletrodos , Campos Eletromagnéticos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , PPAR gama/agonistas , PPAR gama/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Pioglitazona/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
5.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063554

RESUMO

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1ß, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Anilidas/farmacologia , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Tiadiazóis/farmacologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/virologia , Anilidas/uso terapêutico , Animais , COVID-19/complicações , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Imuno-Histoquímica , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/uso terapêutico , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tiadiazóis/uso terapêutico , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
6.
Biomed Res Int ; 2021: 6662704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159197

RESUMO

Objective: Secretion of glucagon-like peptide 1 (GLP-1) and its effect on target organs were impaired in individuals with obesity. However, its mechanism needs to be further studied. We aim to explore the roles of the receptor of GLP-1 (GLP-1R) involved in high-fat-diet- (HFD-) induced kidney damage improved by emodin. Methods: Male C57bl/6 mice were fed with HFD diet and therapied by emodin. NRK-52E cells were cultured and treated with palmitic acid or low-density lipoprotein cholesterol (LDL-C). Emodin was used to remedy the NRK-52E cell damage. GW9662 was administrated to block the function of peroxisome proliferator-activated receptor γ (PPAR-γ). GLP-1 in the plasma was measured by ELISA. PPAR-γ and GLP-1R in the kidney and NRK-52E cells were detected by western blotting. The interaction between PPAR-γ protein and GLP-1R promoter regions was observed by chromatin immunoprecipitation (ChIP). Results: Postprandial GLP-1 levels in plasma, as well as PPAR-γ and GLP-1R, decreased in kidney tissue of HFD mice, while they were reserved by emodin treatment. Although PPAR-γ and GLP-1R were not downregulated by LDL-C, they were suppressed by palmitic acid. Interestingly, GLP-1R mRNA was detected by PCR in the mixture pulled down with PPAR-γ antibody. Additionally, downregulation of PPAR-γ and GLP-1R by palmitic acid was remanded by emodin. Moreover, GW9662, an inhibitor of PPAR-γ, abolished the protective effect of emodin. Conclusion: The kidney damage of HFD mice seems to be alleviated by emodin via the upregulation of GLP-1R in kidney tissue.


Assuntos
Dieta Hiperlipídica , Emodina/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Nefropatias/metabolismo , Anilidas/farmacologia , Animais , Peso Corporal , LDL-Colesterol/metabolismo , Ensaio de Imunoadsorção Enzimática , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/antagonistas & inibidores , Ácido Palmítico/farmacologia , Regiões Promotoras Genéticas , Regulação para Cima
7.
Neurosci Bull ; 37(10): 1412-1426, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34142331

RESUMO

Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.


Assuntos
Hemorragia Cerebral , Hematoma , Receptor X Retinoide alfa , Anilidas/farmacologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hematoma/tratamento farmacológico , Humanos , Macrófagos , Microglia , Neuroproteção , PPAR gama
8.
Sci Rep ; 11(1): 12466, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127734

RESUMO

Chordomas are rare slow growing, malignant bone tumors of the axial skeleton with no approved medical treatment. As the majority of chordomas express cMET and its ligand, HGF, and crosstalks between EGFR and MET-signaling exist, we aimed to explore cMET activity in chordoma cell lines and clinical samples. We investigated nine chordoma patients and four chordoma cell lines for cMET expression. Two clival and two sacral chordoma cell lines were tested for chromosomal abnormalities of the MET gene locus; we studied the influence of HGF on the autocrine secretion and migration behavior, as well as protein expression and phosphorylation. Two MET/ALK inhibitors were investigated for their effects on cell viability, cell cycle, cyclin alterations, apoptosis, and downstream signaling pathways. Moderate and strong expression of membrane and cytoplasmic cMET in chordoma patients and cell lines used, as well as concentration-dependent increase in phospho cMET expression after HGF stimulation in all four chordoma cell lines was shown. U-CH2, MUG-Chor1, and UM-Chor1 are polysomic for MET. Chordoma cell lines secreted EGF, VEGF, IL-6, and MMP9 upon HGF-stimulation. Sacral cell lines showed a distinct HGF-induced migration. Both inhibitors dose-dependently inhibited cell growth, induce apoptosis and cell-cycle arrest, and suppress downstream pathways. Heterogeneous responses obtained in our in vitro setting indicate that cMET inhibitors alone or in combination with other drugs might particularly benefit patients with sacral chordomas.


Assuntos
Cordoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Sacro/patologia , Neoplasias da Base do Crânio/tratamento farmacológico , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Anilidas/farmacologia , Anilidas/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cordoma/genética , Cordoma/patologia , Fossa Craniana Posterior , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Base do Crânio/patologia
9.
Eur J Med Chem ; 221: 113481, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33945934

RESUMO

Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chemistry campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, intraperitoneal administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.


Assuntos
Anilidas/farmacologia , Proteína Quinase CDC2/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Anilidas/síntese química , Anilidas/química , Animais , Proteína Quinase CDC2/metabolismo , Células Cultivadas , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
10.
Cell Death Dis ; 12(5): 483, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986262

RESUMO

Osteoarthritis (OA) is a common articular degenerative disease characterized by loss of cartilage matrix and subchondral bone sclerosis. Kartogenin (KGN) has been reported to improve chondrogenic differentiation of mesenchymal stem cells. However, the therapeutic effect of KGN on OA-induced cartilage degeneration was still unclear. This study aimed to explore the protective effects and underlying mechanisms of KGN on articular cartilage degradation using mice with post-traumatic OA. To mimic the in vivo arthritic environment, in vitro cultured chondrocytes were exposed to interleukin-1ß (IL-1ß). We found that KGN barely affected the cell proliferation of chondrocytes; however, KGN significantly enhanced the synthesis of cartilage matrix components such as type II collagen and aggrecan in a dose-dependent manner. Meanwhile, KGN markedly suppressed the expression of matrix degradation enzymes such as MMP13 and ADAMTS5. In vivo experiments showed that intra-articular administration of KGN ameliorated cartilage degeneration and inhibited subchondral bone sclerosis in an experimental OA mouse model. Molecular biology experiments revealed that KGN modulated intracellular reactive oxygen species in IL-1ß-stimulated chondrocytes by up-regulating nuclear factor erythroid 2-related factor 2 (NRF2), while barely affecting its mRNA expression. Microarray analysis further revealed that IL-1ß significantly up-regulated miR-146a that played a critical role in regulating the protein levels of NRF2. KGN treatment showed a strong inhibitory effect on the expression of miR-146a in IL-1ß-stimulated chondrocytes. Over-expression of miR-146a abolished the anti-arthritic effects of KGN not only by down-regulating the protein levels of NRF2 but also by up-regulating the expression of matrix degradation enzymes. Our findings demonstrate, for the first time, that KGN exerts anti-arthritic effects via activation of the miR-146a-NRF2 axis and KGN is a promising heterocyclic molecule to prevent OA-induced cartilage degeneration.


Assuntos
Anilidas/uso terapêutico , MicroRNAs/metabolismo , Osteoartrite/tratamento farmacológico , Ácidos Ftálicos/uso terapêutico , Anilidas/farmacologia , Animais , Diferenciação Celular , Modelos Animais de Doenças , Progressão da Doença , Humanos , Masculino , Camundongos , Ácidos Ftálicos/farmacologia
11.
J Cell Mol Med ; 25(11): 4950-4961, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33939252

RESUMO

Elevated expression of multiple growth factors and receptors including c-Met and VEGFR has been reported in gastric adenocarcinoma (GAC) and thus provides a potentially useful therapeutic target. The therapeutic efficacy of foretinib, a c-Met/VEGFR2 inhibitor, was determined in combination with nanoparticle paclitaxel (NPT) in GAC. Animal studies were conducted in NOD/SCID mice in subcutaneous and peritoneal dissemination xenografts. The mechanism of action was assessed by Immunohistochemical and Immunoblot analyses. In c-Met overexpressing MKN-45 cell-derived xenografts, NPT and foretinib demonstrated inhibition in tumour growth, while NPT plus foretinib showed additive effects. In c-Met low-expressing SNU-1 or patient-derived xenografts, the foretinib effect was smaller, while NPT had a similar effect compared with MKN-45, as NPT plus foretinib still exhibited an additive response. Median mice survival was markedly improved by NPT (83%), foretinib (100%) and NPT plus foretinib (230%) in peritoneal dissemination xenografts. Subcutaneous tumour analyses exhibited that foretinib increased cancer cell death and decreased cancer cell proliferation and tumour vasculature. NPT and foretinib suppressed the proliferation of GAC cells in vitro and had additive effects in combination. Further, foretinib caused a dramatic decrease in phosphorylated forms of c-Met, ERK, AKT and p38. Foretinib led to a decrease in Bcl-2, and an increase in p27, Bax, Bim, cleaved PARP-1 and cleaved caspase-3. Thus, these findings highlight the antitumour impact of simultaneous suppression of c-Met and VEGFR2 signalling in GAC and its potential to enhance nanoparticle paclitaxel response. This therapeutic approach might lead to a clinically beneficial combination to increase GAC patients' survival.


Assuntos
Anilidas/farmacologia , Sinergismo Farmacológico , Nanopartículas/administração & dosagem , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Proliferação de Células , Combinação de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Nanopartículas/química , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Carbohydr Polym ; 266: 118123, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34044939

RESUMO

In this study, we fabricated two different arrangements of laminated composite scaffolds based on Alginate:Alginate sulfate hydrogel, PCL:Gelatin electrospun mat, and Kartogenin-PLGA nanoparticles (KGN-NPs). The optimized composite scaffold revealed a range of advantages such as improved mechanical features as well as less potential of damage (less dissipated energy), interconnected pores of hydrogel and fiber with adequate pore size, excellent swelling ratio, and controlled biodegradability. Furthermore, the synthesized KGN-NPs with spherical morphology were incorporated into the composite scaffold and exhibited a linear and sustained release of KGN within 30 days with desirable initial burst reduction (12% vs. 20%). Additionally, the cytotoxicity impact of the composite was evaluated. Resazurin assay and Live/Dead staining revealed that the optimized composite scaffold has no cytotoxic effect and could improve cell growth. Overall, according to the enhanced mechanical features, suitable environment for cellular growth, and sustained drug release, the optimized scaffold would be a good candidate for tissue regeneration.


Assuntos
Alginatos/química , Portadores de Fármacos/química , Hidrogéis/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Nanofibras/química , Tecidos Suporte/química , Anilidas/química , Anilidas/farmacologia , Liberação Controlada de Fármacos , Gelatina/química , Humanos , Nanopartículas/química , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Engenharia Tecidual/instrumentação , Engenharia Tecidual/métodos
13.
Sci Rep ; 11(1): 10956, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34040090

RESUMO

Triple-negative breast cancer (TNBC) is a highly malignant type of breast cancer and lacks effective therapy. Targeting cysteine-dependence is an emerging strategy to treat the mesenchymal TNBC. However, many TNBC cells are non-mesenchymal and unresponsive to cysteine deprivation. To overcome such resistance, three selective HDAC6 inhibitors (Tubacin, CAY10603, and Tubastatin A), identified by epigenetic compound library screening, can synergize with cysteine deprivation to induce cell death in the non-mesenchymal TNBC. Despite the efficacy of HDAC6 inhibitor, knockout of HDAC6 did not mimic the synthetic lethality induced by its inhibitors, indicating that HDAC6 is not the actual target of HDAC6 inhibitor in this context. Instead, transcriptomic profiling showed that tubacin triggers an extensive gene transcriptional program in combination with erastin, a cysteine transport blocker. Notably, the zinc-related gene response along with an increase of labile zinc was induced in cells by the combination treatment. The disturbance of zinc homeostasis was driven by PKCγ activation, which revealed that the PKCγ signaling pathway is required for HDAC6 inhibitor-mediated synthetic lethality. Overall, our study identifies a novel function of HDAC6 inhibitors that function as potent sensitizers of cysteine deprivation and are capable of abolishing cysteine-independence in non-mesenchymal TNBC.


Assuntos
Anilidas/farmacologia , Carbamatos/farmacologia , Cisteína/fisiologia , Células Epiteliais/efeitos dos fármacos , Desacetilase 6 de Histona/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Proteínas de Neoplasias/fisiologia , Oxazóis/farmacologia , Transcrição Genética/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisteína/administração & dosagem , Cisteína/deficiência , Ativação Enzimática/efeitos dos fármacos , Feminino , Técnicas de Inativação de Genes , Células HEK293 , Desacetilase 6 de Histona/genética , Homeostase , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Piperazinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/fisiologia , Bibliotecas de Moléculas Pequenas , Transcriptoma , Neoplasias de Mama Triplo Negativas/patologia , Zinco/metabolismo
14.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924361

RESUMO

TRPM7 plays an important role in cellular Ca2+, Zn2+ and Mg2+ homeostasis. TRPM7 channels are abundantly expressed in ameloblasts and, in the absence of TRPM7, dental enamel is hypomineralized. The potential role of TRPM7 channels in Ca2+ transport during amelogenesis was investigated in the HAT-7 rat ameloblast cell line. The cells showed strong TRPM7 mRNA and protein expression. Characteristic TRPM7 transmembrane currents were observed, which increased in the absence of intracellular Mg2+ ([Mg2+]i), were reduced by elevated [Mg2+]i, and were inhibited by the TRPM7 inhibitors NS8593 and FTY720. Mibefradil evoked similar currents, which were suppressed by elevated [Mg2+]i, reducing extracellular pH stimulated transmembrane currents, which were inhibited by FTY720. Naltriben and mibefradil both evoked Ca2+ influx, which was further enhanced by the acidic intracellular conditions. The SOCE inhibitor BTP2 blocked Ca2+ entry induced by naltriben but not by mibefradil. Thus, in HAT-7 cells, TRPM7 may serves both as a potential modulator of Orai-dependent Ca2+ uptake and as an independent Ca2+ entry pathway sensitive to pH. Therefore, TRPM7 may contribute directly to transepithelial Ca2+ transport in amelogenesis.


Assuntos
Ameloblastos/metabolismo , Cálcio/metabolismo , Canais de Cátion TRPM/metabolismo , Ameloblastos/citologia , Ameloblastos/efeitos dos fármacos , Anilidas/farmacologia , Animais , Linhagem Celular , Humanos , Concentração de Íons de Hidrogênio , Incisivo/citologia , Ativação do Canal Iônico/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Mibefradil/farmacologia , Camundongos , Modelos Biológicos , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Ratos , Tiadiazóis/farmacologia
15.
Food Chem Toxicol ; 152: 112183, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33836209

RESUMO

T-2 toxin, the most virulent toxin produced by the Fusarium genus, is thought to be the main cause of fatal cardiomyopathy known as Keshan disease. However, the mechanisms of T-2 toxin-induced cardiac toxicity and possible targets for its treatment remain unclear. In the present study, male Wistar rats were administered with 2 mg/kg b. w. T-2 toxin (i.g.) and sacrificed on day 7 after exposure. The hematological indices (CK, LDH) and electrocardiogram were significantly abnormal, the ultrastructure of mitochondria in the heart was changed, and the percentage of collagen area was significantly increased in the T-2 toxin-treated group. Meanwhile, T-2 toxin activated the TGF-ß1/Smad2/3 signalling pathway, and also activated PPAR-γ expression in rats and H9C2 cells. Further application of PPAR-γ agonist (pioglitazone) and antagonist (GW9662) in H9C2 cells revealed that the up-regulation of PPAR-γ expression induced by T-2 toxin is a self-preservation phenomenon, and increasing exogenous PPAR-γ can alleviate the increase in TGF-ß1 caused by T-2 toxin, thereby playing a role in relieving cardiac fibrosis. These findings for the first time demonstrate that T-2 toxin can regulate the expression of PPAR-γ and that PPAR-γ has the potential to serve as an effective therapeutic target in T-2 toxin-induced cardiac fibrosis of rats.


Assuntos
Cardiomiopatias/metabolismo , Fibrose/metabolismo , PPAR gama/metabolismo , Toxina T-2/toxicidade , Anilidas/farmacologia , Animais , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Linhagem Celular , Colágeno/metabolismo , Fibrose/induzido quimicamente , Fibrose/complicações , Fibrose/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Pioglitazona/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809722

RESUMO

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REarranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti-tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ-CRC-1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. In vivo, the anti-angiogenic potential of VAN and CAB is evaluated in Tg(fli1a:EGFP)y1 transgenic fluorescent zebrafish embryos by analyzing the effects on the physiological development of the sub-intestinal vein plexus and the tumor-induced angiogenesis after TT and MZ-CRC-1 xenotransplantation. VAN and CAB exert comparable effects on TT and MZ-CRC-1 viability inhibition and cell cycle perturbation, and stimulated apoptosis with a prominent effect by VAN in MZ-CRC-1 and CAB in TT cells. Regarding zebrafish, both drugs inhibit angiogenesis in a dose-dependent manner, in particular CAB shows a more potent anti-angiogenic activity than VAN. To conclude, although VAN and CAB show comparable antiproliferative effects in MTC, the anti-angiogenic activity of CAB appears to be more relevant.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anilidas/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Peixe-Zebra/fisiologia , Anilidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Neuroendócrino/irrigação sanguínea , Carcinoma Neuroendócrino/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/efeitos dos fármacos , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Piridinas/farmacologia , Neoplasias da Glândula Tireoide/irrigação sanguínea , Neoplasias da Glândula Tireoide/patologia , Peixe-Zebra/embriologia
17.
Molecules ; 26(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926033

RESUMO

A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.


Assuntos
Antagonistas de Androgênios/química , Anilidas/química , Nitrilas/química , Receptores Androgênicos/química , Talidomida/química , Compostos de Tosil/química , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Sítios de Ligação , Linhagem Celular , Técnicas de Química Sintética , Humanos , Modelos Biológicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nitrilas/farmacologia , Ligação Proteica , Proteólise/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Talidomida/farmacologia , Compostos de Tosil/farmacologia
18.
Bioorg Chem ; 111: 104872, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33838560

RESUMO

Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC50 = 4.52 ± 0.28 µM; SK: IC50 = 7.62 ± 0.26 µM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/ß-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure-activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Ésteres/farmacologia , Naftoquinonas/farmacologia , Anilidas/síntese química , Anilidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Humanos , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
19.
Int J Mol Med ; 47(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33907825

RESUMO

The epithelial­mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is an important underlying mechanism of proliferative vitreoretinopathy (PVR). We previously found that L­carnitine (ß­hydroxy­Î³­N-trimethylammonium­butyrate, LC) was significantly lower during the transforming growth factor­ß1 (TGF­ß1)­induced EMT process in ARPE­19 cells. The present study assessed the role of LC in the EMT of RPE cells. The migration of RPE cells was detected using a Transwell migration assay. Then, EMT­related biomarkers were measured via western blotting, immunofluorescence and reverse transcription­quantitative PCR. It was observed that LC attenuated the TGF­ß1­induced downregulation of the epithelial markers E­Cadherin and zonula occludens­1, as well as the expression of mesenchymal markers fibronectin and α­smooth muscle actin. Meanwhile, LC blocked Erk1/2 and JNK pathways in the EMT of RPE cells. Moreover, treatment with a peroxisome proliferator­activated receptor Î³ (PPARγ) inhibitor prevented the effect of LC on EMT. Taken together, these data suggested that LC attenuated EMT induced by TGF­ß1 via inhibition of the Erk1/2 and JNK pathways and upregulation of PPARγ expression.


Assuntos
Carnitina/farmacologia , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , PPAR gama/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Fator de Crescimento Transformador beta1/farmacologia , Anilidas/farmacologia , Antracenos/farmacologia , Butadienos/farmacologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , NF-kappa B/metabolismo , Nitrilas/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Proteínas Smad/metabolismo
20.
Cancer Chemother Pharmacol ; 87(6): 827-842, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33688998

RESUMO

PURPOSE: Glioblastoma multiforme (GBM) is one of the most aggressive human cancers. The c-MET receptor tyrosine kinase (RTK) which is frequently deregulated in GBM is considered as a promising target for GBM treatment. The c-MET plays a key role in cell proliferation, cell cycle progression, invasion, angiogenesis, and metastasis. Here, we investigated the anti-tumour activity of foretinib, a c-MET inhibitor, on three human GBM cells (T98G, U87MG and U251). METHODS: Anti-proliferative effect of foretinib was determined using MTT, crystal violet staining, and clonogenic assays. PI and Annexin V/PI staining flow cytometry were used to evaluate the effects of foretinib on cell cycle and apoptosis, respectively. Scratch assay, qRT-PCR, western blot, and zymography analyses were applied to elucidate the molecular mechanisms underlying the anti-tumour activity of foretinib. RESULTS: Foretinib treatment reduced phosphorylation of c-MET on T98G and U251 cells, but not in U87MG cells. The highest inhibitory effect was observed in T98G cells (IC50 = 4.66 ± 0.29 µM) and the lowest one in U87MG cells (IC50 = 29.99 ± 1.31 µM). The results showed that foretinib inhibited the proliferation of GBM cells through a G2/M cell cycle arrest and mitochondrial-mediated apoptosis in association with alternation in expression of the related genes and protein-regulated G2/M phase and apoptosis. Foretinib diminished GBM cell invasion through downregulation of the proteolytic cascade of MMP2, uPA and uPAR and epithelial-mesenchymal transition (EMT)-related genes. A different GBM cell sensitivity pattern was noticeable in all experiments which demonstrated T98G as a sensitive and U87MG as a resistant phenotype to foretinib treatment. CONCLUSION: The results indicated that foretinib might have the therapeutic potential against human GBM which deserve further investigation.


Assuntos
Anilidas/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinolinas/farmacologia , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Transdução de Sinais/efeitos dos fármacos
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