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1.
Medicine (Baltimore) ; 98(43): e17457, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651849

RESUMO

The activity of p70S6 kinase located downstream of the mammalian target of rapamycin (mTOR) pathway is sensitive to mTOR inhibitors. However, the methods of assessing p70S6 kinase activity are still unclear. This study aimed to investigate p70S6 kinase activity in CD4-positive cells of liver transplant patients.Liver transplant patients treated with mTOR inhibitors were recruited from Beijing Chaoyang Hospital between October 2014 and October 2016. The influence of mycophenolic acid (MPA) derivatives and prednisone on p70S6 kinase phosphorylation in CD4-positive cells was examined in liver transplant patients and healthy controls (HCs). The phosphorylation of p70S6K in CD4 + CD25 regulatory T cells (Treg cells) and CD4 + CD25- T effector cells was analyzed by phospho-flow cytometry.The phospho-flow technique detected a significant loss of p70S6 kinase phosphorylation in CD4-positive cells of patients treated with mTOR inhibitors compared with HCs. MPA derivatives and prednisone did not affect p70S6 kinase phosphorylation significantly. No significant difference in p70S6 kinase phosphorylation was observed when the whole blood was stored within 3 hours at room temperature. The phosphorylation of p70S6K was significantly lower in CD4 + CD25 Treg cells than in CD4 + CD25-T effector cells in HCs. After liver transplant patients were treated with mTOR inhibitors, p70S6K phosphorylation was more reduced in CD4 + CD25-T effector cells than in CD4 + CD25 Treg cells.The presence of phosphorylation of p70S6 kinase in CD4-positive cells was reduced in liver transplant patients who were treated by mTOR inhibitors.


Assuntos
Linfócitos T CD4-Positivos/enzimologia , Inibidores Enzimáticos/farmacologia , Transplante de Fígado , Ácido Micofenólico/farmacologia , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Resultado do Tratamento , Adulto Jovem
2.
Expert Opin Drug Metab Toxicol ; 15(9): 767-774, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478386

RESUMO

Introduction: The phosphatidylinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway has emerged as an important target in cancer therapy. Numerous PI3K/AKT/mTOR pathway inhibitors are extensively studied; some are used clinically, but most of these drugs are undergoing clinical trials. Potential adverse effects, such as severe hepatotoxicity and pneumonitis, have largely restricted the application and clinical significance of these inhibitors. A summary of mechanisms underlying the adverse effects is not only significant for the development of novel PI3K/AKT/mTOR inhibitors but also beneficial for the optimal use of existing drugs. Areas covered: We report a profile of the adverse effects, which we consider the class effects of PI3K/AKT/mTOR inhibitors. This review also discusses potential molecular toxicological mechanisms of these agents, which might drive future drug discovery. Expert opinion: Severe toxicities associated with PI3K/AKT/mTOR inhibitors hinder their approval and limit long-term clinical application of these drugs. A better understanding regarding PI3K/AKT/mTOR inhibitor-induced toxicities is needed. However, the mechanisms underlying these toxicities remain unclear. Future research should focus on developing strategies to reduce toxicities of approved inhibitors as well as accelerating new drug development. This review will be useful to clinical, pharmaceutical, and toxicological researchers.


Assuntos
Antineoplásicos/efeitos adversos , Descoberta de Drogas/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Humanos , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
3.
Chem Biol Interact ; 311: 108793, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421117

RESUMO

Polyphyllin I (PPI), a bioactive component extracted from Paris polyphylla, was reported to have potent anticancer activities in previous studies. However, there were few reports on the effects and underlying mechanism of PPI in human acute myeloid leukemia cells. The present study demonstrated that PPI had an inhibitory effect through inducing apoptosis and autophagy in THP-1 and NB4 cells. PPI induced apoptosis via activating JNK pathway, as evidenced by the decreased Bcl-2 levels and increased Bax, cleaved-caspase-3 and phosphorylated-JNK expressions. In addition, PPI promoted autophagy as evidenced with increased expressions of LC3-II and Beclin-1 in western blot and autophagic vacuoles in MDC staining, which was associated with the inhibition of AKT-mTOR pathway. Furthermore, JNK inhibitor SP600125 and autophagy inhibitor 3-MA were employed to evaluate the role of apoptosis and autophagy in PPI-induced cell death. We found that autophagy and apoptosis were both causes of cell death induced by PPI. These data suggested that PPI could be a potent therapeutic agent for the treatment of human acute myeloid leukemia.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diosgenina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Diosgenina/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Life Sci ; 233: 116748, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31412263

RESUMO

AIMS: Resveratrol is a polyphenolic compound that has received much attention for its use in ameliorating various systemic pathological conditions. The present study was performed to investigate whether the resveratrol alleviated cardiac hypertrophy and functional remodelling by regulating autophagy. MATERIALS AND METHODS: Male rats were exposed to CIH 8 h/day for five weeks and/or intragastric administration of resveratrol daily. The morphological and echocardiography were used to evaluate the cardiac protective effects. The apoptosis was detected by TUNEL staining. The biochemical assessments were used to evaluate oxidative stress. Further, the effect of resveratrol on autophagy and PI3K/AKT/mTOR pathway was investigated. KEY FINDINGS: The CIH group exhibited increased heart weight/body weight and left ventricle weight/body weight ratios, which was accompanied by left ventricular remodelling. Echocardiography analysis showed that CIH-treated rats had significantly higher left ventricular posterior wall thickness, ejection fraction and fractional shortening than those of controls. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group versus the control. The autophagy marker Beclin-1 was elevated, while p62 was decreased by CIH treatment. Resveratrol treatment significantly improved cardiac function and alleviated cardiac hypertrophy, oxidative stress, and apoptosis in CIH rats. Further results indicated that PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway played a role in the activation of autophagy by resveratrol after CIH stimulation. SIGNIFICANCE: In conclusion, resveratrol supplementation during CIH upregulates autophagy by targeting the PI3K/AKT/mTOR pathway, which appears to be beneficial for resisting cardiac hypertrophy.


Assuntos
Cardiomegalia/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Hipóxia/complicações , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Resveratrol/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Apoptose , Autofagia , Cardiomegalia/etiologia , Cardiomegalia/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
5.
Scand J Immunol ; 90(5): e12810, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325389

RESUMO

MicroRNAs (miRNAs) play a vital role in the occurrence and development of many human diseases, including systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by the production of autoantibodies against nuclear antigens and multiorgan involvement. Study of miRNAs involved in SLE provides new insights into the pathogenesis of SLE and might lead to the identification of new therapeutic interventions. The aim of this study was to investigate the effect of miR-183 injection on the progression of SLE by using MRL/lpr mouse model. The expression levels of miR-183 and mTOR mRNA were detected by quantitative real-time PCR assay. The effect of miR-183 on the course of spontaneous disease progression in the MRL/lpr mice was examined by intraperitoneal injection of miR-183 into mice and followed by monitoring lifespan, anti-dsDNA antibody levels, urinary albumin levels, blood urea nitrogen (BUN) levels, and Tregs and Th17 cell population. We found that miR-183 injection resulted in reduction of anti-DNA antibody and immune complex component levels, restoration of Tregs and Th17 cell population and prolongation of survival. Our findings suggest that miR-183 injection may serve as an effective therapeutic treatment for delaying or easing pathologic features of SLE.


Assuntos
Nefrite Lúpica/terapia , MicroRNAs/genética , MicroRNAs/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Adulto , Albuminúria/urina , Animais , Anticorpos Antinucleares/sangue , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Feminino , Humanos , Nefrite Lúpica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Células Th17/imunologia
6.
Eur J Med Chem ; 178: 667-686, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31228810

RESUMO

PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.


Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Descoberta de Drogas , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzoxazinas/administração & dosagem , Benzoxazinas/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 , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
7.
Cancer Radiother ; 23(5): 423-425, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176579

RESUMO

The addition of everolimus to exemestane is recommended in patients with HR+ advanced breast cancer with disease recurrence or progression following prior non-steroidal aromatase inhibitors. We report a case of radiation recall syndrome in a breast cancer patient, after introduction of everolimus. A woman with a right breast cancer underwent a mastectomy, then adjuvant chemotherapy, radiation therapy and hormonotherapy. In a phase III trial (UNIRAD protocol), she received everolimus 5 months after radiation therapy. Seven days after introduction, she was suffering from a radiation recall syndrome with exacerbation skin reactions. The exact pathophysiological mechanism of radiation recall syndrome is unknown. The combination of radiation therapy and mTor inhibitor, even sequentially, should be done with caution as several cases have already been reported.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Lobular/radioterapia , Estrogênios , Everolimo/efeitos adversos , Linfocele/etiologia , Neoplasias Hormônio-Dependentes/radioterapia , Progesterona , Radiodermatite/induzido quimicamente , Radioterapia de Intensidade Modulada/efeitos adversos , Androstadienos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carcinoma Lobular/química , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/cirurgia , Everolimo/administração & dosagem , Feminino , Humanos , Irradiação Linfática , Mastectomia , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/química , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/cirurgia , Radiodermatite/etiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
8.
Expert Opin Investig Drugs ; 28(7): 583-592, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215251

RESUMO

Introduction: PDAC is a lethal malignancy with a clear unmet need; almost all patients fail 1st, 2nd, and 3rd line multi-agent cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) has been identified as a key signaling node enhancing tumor survival and drug resistance in PDAC; hence, it is considered a promising therapeutic target. Areas covered: We comprehensively reviewed the evidence from preclinical and phase I and II clinical trials, based on the authors'clinical experience and a PubMed, Cochrane library, Embase, and Google Scholar search everolimus + pancreatic cancer. Expert opinion: Everolimus has not demonstrated efficacy in PDAC; however, an mTOR inhibitor in combination with stroma-targeted therapies may be a promising area to explore in clinical trials.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Everolimo/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/patologia , Resistencia a Medicamentos Antineoplásicos , Everolimo/farmacologia , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/patologia , Sobrevida , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
9.
J Cardiovasc Surg (Torino) ; 60(4): 439-449, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31062571

RESUMO

Drug-eluting stent (DES) are the mainstay therapy for the treatment of coronary artery disease. Stent design and drug-elution strategies have evolved over the years leading to the last generation DES which shows optimal safety and efficacy outcome. Peripheral arteries have different mechanical and biological features and the lessons learned from the coronary field have been difficult to introduce into the development of peripheral vascular technologies. First, due to its complex biomechanical behavior the use of metallic stents is limited in some vascular segments (i.e., distal superficial fermoral artery [SFA]). Also, peripheral vascular atherosclerosis is different containing higher levels of plaque burden and calcium. Finally, peripheral arterial disease tends to be more aggressive including longer lesions and higher incidence of total chronic occlusion. In general terms, restenosis in the peripheral vascular territory is more aggressive and occurs at a later time (~12 months) requiring a different pharmacokinetic profile compared to coronary technologies. Several strategies have been evaluated in the peripheral arteries raging from the bare metal stent to the drug coated balloon and drug eluting stent with outcome varying depending on the different field of application (i.e. SFA and below-the-knee). Results coming from the clinical trial are encouraging but further studies and direct comparison among the different technologies are demanded to determine the best therapy for peripheral vascular disease.


Assuntos
Paclitaxel/administração & dosagem , Doença Arterial Periférica/terapia , Sirolimo/administração & dosagem , Stents , Sistemas de Liberação de Medicamentos , Stents Farmacológicos , Everolimo/administração & dosagem , Artéria Femoral/cirurgia , Humanos , Doença Arterial Periférica/tratamento farmacológico , Polímeros , Prevenção Secundária/métodos , Serina-Treonina Quinases TOR/antagonistas & inibidores
10.
Comput Biol Chem ; 80: 351-363, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31085426

RESUMO

mTOR has become a promising target for many types of cancer like breast, lung and renal cell carcinoma. CoMFA, CoMSIA, Topomer CoMFA and HQSAR were performed on the series of 39 triazine morpholino derivatives. CoMFA analysis showed q2 value of 0.735, r2cv value of 0.722 and r2pred value of 0.769. CoMSIA analysis (SEHD) showed q2 value of 0.761, r2cv value of 0.775 and r2pred value of 0.651. Topomer CoMFA analysis showed q2 value of 0.693, r2 (conventional correlation coefficient) value of 0.940 and r2pred value of 0.720. HQSAR analysis showed q2,r2and r2pred values of 0.694, 0.920 and 0.750, respectively. HQSAR analysis with the combination of atomic number (A), bond type (B) and atomic connections showed q2 and r2 values of 0.655 and 0.891, respectively. Contour maps from all studies provided significant insights. Molecular docking studies with molecular dynamics simulations were carried out on the highly potent compound 36. Furthermore, four acridine derivatives were designed and docking results of these designed compounds showed the same interactions as that of the standard PI-103 which proved the efficiency of 3D-QSAR and MD/MS study. In future, this study might be useful prior to synthesis for the designing of novel mTOR inhibitors.


Assuntos
Morfolinas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Triazinas/metabolismo , Acridinas/química , Acridinas/metabolismo , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Conjuntos de Dados como Assunto , Desenho de Drogas , Humanos , Ligações de Hidrogênio , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Morfolinas/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Serina-Treonina Quinases TOR/química , Triazinas/química
11.
J Mol Histol ; 50(3): 273-283, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049797

RESUMO

Recent studies have demonstrated that IGF-1 modulates the pluripotent differentiation of dental pulp stem cells (DPSCs). Although mTOR pathway activation has been showed as responsible for IGF-1 induced pluripotent differentiation, the mechanism that the IGF-1-mTOR pathway induces the neural differentiation of DPSCs is still unclear. In our research, we have demonstrated that 0-10 ng/mL IGF-1 had no obvious effect on the proliferation of DPSCs, but IGF-1 nonetheless enhances the neural differentiation of DPSCs in a dose-dependent manner. Simultaneously, we found that phosphorylated mTOR was up-regulated, which indicated the involvement of mTOR in the process. Rapamycin, an inhibitor of mTOR activity, can reverse the effect of DPSCs stimulated by IGF-1. Next, we studied the role of mTORC1 and mTORC2, two known mTOR complexes, in the neural differentiation of DPSCs. We found that inhibition of mTORC1 can severely restricts the neural differentiation of DPSCs. However, inhibition of mTORC2 has the opposite effect. This latter effect disappears when both rictor and mTOR are inhibited, showing that the mTORC2 effect is mTORC1 dependent. This study has expanded the role of mTOR in DPSCs neural differentiation regulated by IGF-1.


Assuntos
Diferenciação Celular/genética , Polpa Dentária/enzimologia , Fator de Crescimento Insulin-Like I/genética , Células-Tronco/efeitos dos fármacos , Adolescente , Adulto , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células , Polpa Dentária/citologia , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/crescimento & desenvolvimento , Feminino , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Adulto Jovem
12.
Gynecol Oncol ; 154(1): 218-227, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31053403

RESUMO

OBJECTIVES: NR4A1 is overexpressed in many solid tumors, and the objectives of this study were to investigate the expression and functional role of this receptor in endometrial cancer cells and demonstrate that NR4A1 antagonist inhibit mTOR. METHODS: Ishikawa and Hec-1B endometrial cells were used as models to investigate the parallel effects of NR4A1 knockdown by RNA interference (siNR4A1) and treatment with bis-indole-derived NR4A1 ligands (antagonists) on cell growth and survival by determining cell numbers and effects on Annexin V staining. Western blot analysis of whole cell lysates was used to determine effects of these treatments on expression of growth promoting, survival and apoptotic genes and mTOR signaling. Effects of NR4A1 antagonists on tumor growth were determined in athymic nude mice bearing Hec-1B cells as xenografts. RESULTS: siNR4A1 or treatment with bis-indole-derived NR4A1 antagonists inhibited growth of endometrial cancer cells in vitro and endometrial tumors in vivo and this was accompanied by decreased expression of growth promoting and survival genes and mTOR inhibition. CONCLUSIONS: NR4A1 exhibited pro-oncogenic activity in endometrial cells due, in part, to regulation of cell growth, survival and mTOR signaling, and all of these pathways and their associated gene products were inhibited after treatment with bis-indole-derived NR4A1 antagonists. Moreover, these compounds also blocked endometrial tumor growth in vivo demonstrating that NR4A1 is a potential novel drug target for treatment of endometrial cancer.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Indóis/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Endométrio/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Ligantes , Camundongos , Camundongos Nus , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Med Chem ; 175: 172-186, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082764

RESUMO

Due to the limitations of existing anti-EV71 targets, we have been eager to discover a new anti-EV71 agent based on mTOR (the mammalian target of rapamycin), which is an important target for finding antiviral agents based on host cells. Torin2 is a second-generation ATP competitive mTOR kinase inhibitor (IC50 = 0.25 nM). Our research team tested the anti-EV71 activity of Torin2 in vitro for the first time. The result showed that Torin2 had significant anti-EV71 activity (IC50 = 0.01 µM). In this study, thirty novel Torin2 derivatives were synthesized and evaluated for anti-EV71 activity. Among them, 11a, 11b, 11d, 11e and 11m displayed similar activity to Torin2. 11e displayed the most potent activity, with an IC50 value of 0.027 µM, which was closest to Torin2, and displayed potent mTOR kinase inhibitory activity. A molecular modeling study showed that 11e interacted with Val2240 and Lys2187 via hydrogen bonds and had a good match with the receptor. Additionally, a mechanism study showed that most of the compounds had significant inhibition for the mTOR pathway substrates p70S6K and Akt. The water solubility test of compounds with potent activity revealed that 11a and 11m were improved by approximately 5-15-fold compared to Torin2. These data suggest that 11a and 11m may be potential candidates for anti-EV71 treatment.


Assuntos
Antivirais/química , Antivirais/farmacologia , Desenho de Drogas , Enterovirus Humano A/efeitos dos fármacos , Naftiridinas/química , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antivirais/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Células Cultivadas , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftiridinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Solubilidade , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
14.
Blood Purif ; 47 Suppl 2: 12-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943481

RESUMO

BACKGROUND/AIMS: α-Klotho is mainly expressed in the kidneys, and its soluble form can prevent vascular calcifications. Inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho. We assessed serial changes in the levels of soluble Klotho (sKlotho) in recipients before and after renal transplantation and investigated the effects of an mTOR inhibitor. METHODS: Serum sKlotho levels were measured in 36 recipients before and 1 year after transplantation and compared between those taking everolimus and those not taking everolimus. RESULTS: sKlotho levels were higher after transplantation than before transplantation (369.3 vs. 211.8 pg/mL). After transplantation, sKlotho levels were significantly higher in recipients taking everolimus than in those not taking everolimus (536.7 vs. 332.4 pg/mL). CONCLUSION: Our results suggest that mTOR inhibition may augment the increase in sKlotho levels in transplant recipients. Further studies are needed to examine whether mTOR inhibitors suppress the development of vascular complications via upregulation of Klotho expression in renal transplant recipients.


Assuntos
Everolimo/uso terapêutico , Glucuronidase/sangue , Imunossupressores/uso terapêutico , Transplante de Rim , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Feminino , Humanos , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Pancreas ; 48(4): 568-573, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946236

RESUMO

OBJECTIVES: The study aimed to investigate the involvement of the mammalian target of rapamycin (mTOR) signaling pathway in orexin-A/OX1 receptor-induced insulin secretion in rat insulinoma INS-1 cells. METHODS: Rat insulinoma INS-1 cells were grown and treated with various concentrations of orexin-A, with or without OX1 receptor-selective antagonist SB674042 or the phosphatidylinositol 3-kinase/mTOR antagonist PF-04691502. Insulin release experiments, Western blot analysis, and statistical analysis were conducted using INS-1 cells. RESULTS: Our results showed that treating cells with orexin-A increased the expression of the OX1 receptor and the phosphorylation of mTOR in a concentration-dependent manner. An increase in insulin secretion was also observed for cells treated with orexin-A. We further demonstrated that the increase in insulin secretion was dependent on the activation of the OX1 receptor and mTOR signaling pathway by using the OX1 receptor-selective antagonist SB674042 or the phosphatidylinositol 3-kinase/mTOR antagonist PF-04691502, which abolished the effects of orexin-A treatment. CONCLUSIONS: Our results concluded that orexin-A/OX1 receptor stimulates insulin secretion by activating AKT and its downstream target, mTOR. Therefore, orexins may regulate the energy balance for cell survival with the involvement of mTOR in this process.


Assuntos
Secreção de Insulina/efeitos dos fármacos , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Insulinoma/metabolismo , Insulinoma/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Piridonas/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tiazóis/farmacologia
16.
J BUON ; 24(1): 310-314, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941986

RESUMO

PURPOSE: To investigate the growth inhibitory effect of Sorghumol on the circulating renal cancers cells and to investigate the underlying mechanisms including its effects on apoptosis, cell cycle phase distribution and m-TOR/PI3K/AKT signalling pathway. METHODS: The antiproliferative effects were assessed by WST-1 and colony formation assay. Apoptosis was detected by the Hoechst and AO/EB staining using fluorescence microscopy. Cell cycle analysis was carried out by flow cytometry. Protein expression was checked by western blotting. RESULTS: The results revealed that Sorghumol inhibited the growth of the renal cancer cell (RCC) line A498 and circulating RCCs. However, more profound effects were observed on the RCC cells. The anticancer effects were found to be due to induction of apoptosis. Moreover, Sorghumol could also caused G2/M cell cycle arrest of the RCC cells. Besides, examination of the effect of Sorghumol on m-TOR/PI3K/AKT revealed that Sorghumol inhibited the expression of p-mTOR, p-PI3K and p-AKT in a concentration-dependent manner. CONCLUSION: Taken together, we conclude that Sorghumol inhibited the proliferation of circulating RCCs and may therefore prove to be an important lead molecule for the treatment of renal cancer.


Assuntos
Neoplasias Renais/tratamento farmacológico , Células Neoplásicas Circulantes/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores
17.
J BUON ; 24(1): 285-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941982

RESUMO

PURPOSE: The purpose of the present study was to investigate the anticancer properties of isoacteoside against OVCAR-3 human ovarian cancer cells. Its effects on apoptosis, reactive oxygen species (ROS) generation, cell invasion, cell cycle arrest and its effects on tumor volume and weight were also evaluated in the current study. METHODS: MTT assay was used to study the cytotoxic effects of the compound on the cell viability. Effects on apoptosis and cell cycle arrest were evaluated by flow cytometry. In vitro wound healing assay and matrigel assay were carried out to study the effects of isoacteoside on cell migration and cell invasion respectively. Non-cancer ovarian cell line SV-40 served as control. RESULTS: Isoacteoside exerted both dose-dependent as well as time-dependent growth inhibitory effects on ovarian cancer cells with IC50 values of 15 µM at 24h incubation. Isoacteoside led to early and late apoptosis induction in these cells. Isoacteoside also led to sub-G1 cell cycle arrest which showed strong dose-dependence. Isoacteoside treatment also led to inhibition of cell migration and cell invasion. The results revealed that OVCAR-3 tumor growth was significantly suppressed by isoacteoside administration, compared with that in the control group. At the end of the 5-week period of isoacteoside treatment, the average tumor growth and volume in the untreated control group were considerably higher than those in the treated groups. CONCLUSION: In brief, the current study indicates that isoacteoside has a great potential in suppressing both in vitro and in vivo ovarian cancer cell growth and can be used as a possible anticancer agent.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glucosídeos/farmacologia , Neoplasias Ovarianas/prevenção & controle , Fenóis/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Camundongos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Asian Pac J Cancer Prev ; 20(4): 1229-1241, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31030499

RESUMO

Breast cancer is the most frequent malignancy among women. It is a heterogeneous disease with different subtypes defined by its hormone receptor. A hormone receptor is mainly concerned with the progression of the PI3K/AKT/ mTOR pathway which is often dysregulated in breast cancer. This is a major signaling pathway that controls the activities such as cell growth, cell division, and cell proliferation. The present study aims to suppress mTOR protein by its various inhibitors and to select one with the highest binding affinity to the receptor protein. Out of 40 inhibitors of mTOR against breast cancer, SF1126 was identified to have the best docking score of -8.705, using Schrodinger Suite which was further subjected for high throughput screening to obtain best similar compound using Lipinski's filters. The compound obtained after virtual screening, ID: ZINC85569445 is seen to have the highest affinity with the target protein mTOR. The same result based on the binding free energy analysis using MM-GBSA showed that the compound ZINC85569445 to have the the highest binding free energy. The next study of interaction between the ligand and receptor protein with the pharmacophore mapping showed the best conjugates, and the ZINC85569445 can be further studied for future benefits of treatment of breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Simulação por Computador , Bases de Dados de Produtos Farmacêuticos , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Ligantes , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/isolamento & purificação , Relação Estrutura-Atividade
19.
Oncol Rep ; 41(6): 3179-3188, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942458

RESUMO

Multidrug resistance (MDR) is a major reason for the failure of acute myeloid leukemia (AML) therapy. Agents that reverse MDR and sensitize AML cells to chemotherapy are of great clinical significance. The present study developed Adriamycin (Adr)­resistant cell lines, namely K562/Adr200 and K562/Adr500, which exhibited MDR. The upregulation of ATP­binding cassette subfamily B member 1 (ABCB1) was confirmed as the mechanism of resistance by reverse transcription­quantitative polymerase chain reaction and western blot analyses. Subsequently, the role of the mammalian target of rapamycin (mTOR) kinase inhibitor, WYE­354, in sensitizing the K562/Adr200 and K562/Adr500 cell lines to Adr was evaluated. At sub­cytotoxic concentrations, WYE­354 increased Adr cytotoxicity in the K562/Adr200 and K562/Adr500 cells. WYE­354 restored Adr sensitivity in the resistant cells by inhibiting ABCB1­mediated substrate efflux, thereby leading to an accumulation of Adr, an increase in Adr­mediated G2/M cell cycle arrest and the induction of apoptosis. Furthermore, WYE­354 stimulated the ATPase activity of ABCB1, which was consistent with in silico predictions using a human ABCB1 mouse homology model, indicating that WYE­354 is a potent substrate of ABCB1. WYE­354 did not regulate the expression of ABCB1 at the concentrations used in the present study. These findings indicate that WYE­354 may be a competitive inhibitor of ABCB1­mediated efflux and a potential candidate in combination with standard chemotherapy for overcoming MDR. Further clinical investigations are warranted to validate this combination in vivo.


Assuntos
Doxorrubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Purinas/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adenosina Trifosfatases/química , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Especificidade por Substrato , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética
20.
Nat Commun ; 10(1): 1897, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015486

RESUMO

The cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase. If the RAS signal is constitutively activated, RUNX3 inhibits cell cycle progression by maintaining R-point-associated genes in an open structure. Our results identify RUNX3 as a pioneer factor for the R-point and reveal the molecular mechanisms by which appropriate chromatin modifiers are selectively recruited to target loci for appropriate R-point decisions.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Cromatina/química , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Animais , Butadienos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Subunidade alfa 3 de Fator de Ligação ao Core/antagonistas & inibidores , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células HEK293 , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Imidazóis/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Nitrilos/farmacologia , Piperazinas/farmacologia , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
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