Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Int J Colorectal Dis ; 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31955218

RESUMO

OBJECTIVE: Postoperative delirium (POD) is a common, but severe complication in elderly patients undergoing surgery for colorectal cancer, but the prevalence and potential risk factors for POD were not well established. Therefore, a meta-analysis was preformed to clarify the prevalence and risk factors of POD in patients undergoing surgery for colorectal cancer. METHODS: PubMed, Embase, and the Cochrane Library were systematically searched on August 2019. Studies were included if they reported the prevalence and risk factors of POD in patients undergoing colorectal cancer surgery. The guidelines for critically appraising studies of prevalence or incidence of a health problem were used to assess the quality of included studies. Pooled odds ratios (ORs) for individual risk factors were estimated using the Mantel-Haenszel methods in random effect model. Sensitive analyses based on different inclusion criteria were conducted to explore whether the current meta-analysis was enough credible and robust. RESULTS: Seventeen studies totaling 4472 patients undergoing colorectal cancer surgery were included. The pooled prevalence of POD is 14% (95% CI = 12-17%). Twelve significant risk factors were identified in pooled analysis including older age (OR = 1.10), sex (OR = 1.87), history of psychiatric disease (OR = 6.47), comorbidities (OR = 2.17), prognostic nutritional index (OR = 1.12), physical status (OR = 1.27), American Society of Anesthesiologists Score (ASA Scores) (OR = 1.65), history of alcohol abuse (OR = 2.23), postoperative pain management (OR = 1.91), perioperative blood transfusion (OR = 2.37), cognitive status (OR = 1.91), and lower serum level of albumin (OR = 0.58). CONCLUSIONS: POD is a frequent complication in patients undergoing surgery with colorectal cancer. Several risk factors including history of psychiatric disease, transfusion, comorbidities, male gender, and old age were significant predictors for POD.

2.
Cell Biol Toxicol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31768838

RESUMO

Inflammation reaction mediated by NLRP3 inflammasome and Nrf2-related oxidative stress are vital participants in the development of diabetic nephropathy (DN) and closely associated to kidney fibrosis. Nrf2, a known antioxidative transcription factor, has been reported to activate NLRP3 inflammasome through its downstream factors (HO-1, NQO1, etc.) recently. AB38b is a newly synthesized biphenyl diester derivative with a Nrf2 activation property. This research aims to evaluate the renal protective effects of AB-38b and to elucidate the anti-inflammation mechanisms involved. Type 2 diabetic mice induced by high fat diet with streptozocin (STZ) and high glucose-cultured mouse glomerular mesangial cells (GMCs) were used in current study. Results showed that administration of AB-38b improved the kidney function while attenuated renal fibrosis progression in diabetic mice together with reducing the extracellular matrix (ECM) accumulation of GMCs cultured in high glucose. Mechanistically, treatment with AB-38b significantly decreased the high level of NLRP3 inflammasome in diabetic condition by inhibiting the ROS/TXNIP/NLRP3 signaling pathway. And meanwhile, AB-38b treatment effectively improved Nrf2 signaling during diabetic condition. Furthermore, knocking down the gene expression of Nrf2 by siRNA in GMCs abolished the inhibition effect of AB-38b on NLRP3 inflammasome activation and ECM accumulation. Taken together, our data suggest that AB-38b was able to improve the renal function of diabetic mice, and the NLRP3 inflammasome inhibition effect of AB-38b was responsible for the renal protective effect. Further exploration indicate that Nrf2 plays pivotal role in AB-38b's attenuation of DN progression through inhibiting NLRP3 inflammasome activation.

3.
Acta Pharmacol Sin ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645661

RESUMO

Extracellular matrix (ECM) deposition following reactive oxygen species (ROS) overproduction has a key role in diabetic nephropathy (DN), thus, antioxidant therapy is considered as a promising strategy for treating DN. Here, we investigated the therapeutic effects of AB38b, a novel synthetic α, ß-unsaturated ketone compound, on the oxidative stress (OS) and ECM accumulation in type 2 diabetes mice, and tried to clarify the mechanisms underlying the effects in high glucose (HG, 30 mM)-treated mouse glomerular mesangial cells (GMCs). Type 2 diabetes model was established in mice with high-fat diet feeding combined with streptozocin intraperitoneal administration. The diabetic mice were then treated with AB38b (10, 20, 40 mg· kg-1· d-1, ig) or a positive control drug resveratrol (40 mg· kg-1· d-1, ig) for 8 weeks. We showed that administration of AB38b or resveratrol prevented the increases in malondialdehyde level, lactate dehydrogenase release, and laminin and type IV collagen deposition in the diabetic kidney. Simultaneously, AB38b or resveratrol markedly lowered the level of Keap1, accompanied by evident activation of Nrf2 signaling in the diabetic kidney. The underlying mechanisms of antioxidant effect of AB38b were explored in HG-treated mouse GMCs. AB38b (2.5-10 µM) or resveratrol (10 µM) significantly alleviated OS and ECM accumulation in HG-treated GMCs. Furthermore, AB38b or resveratrol treatment effectively activated Nrf2 signaling by inhibiting Keap1 expression without affecting the interaction between Keap1 and Nrf2. Besides, AB38b treatment effectively suppressed the ubiquitination of Nrf2. Taken together, this study demonstrates that AB38b ameliorates experimental DN through antioxidation and modulation of Keap1/Nrf2 signaling pathway.

4.
Eur J Med Chem ; 180: 62-71, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301564

RESUMO

Oxidative stress and inflammation are major causes of numerous life-threatening human diseases. In the present study, we synthesized a series of phenylacrylamide derivatives as novel anti-oxidant and anti-inflammatory agents. Biological evaluation showed that compound 6a could more potently protect HBZY-1 mesangial cells from H2O2-caused oxidative stress than positive controls resveratrol and sulforaphane by dose- and time-dependently impairing the ROS accumulation. Preliminary anti-oxidant mechanism studies indicated that compound 6a could activate Nrf2 and increase the protein and mRNA expression of downstream anti-oxidant enzymes, ie. NQO-1, HO-1, GCLM and GCLC. Notably, 6a could inhibit the production of NO and the activity of NF-κB in LPS-stimulated HBZY-1 mesangial cells, indicating its potential anti-inflammatory activity. Interestingly, both effects could be significantly attenuated by Nrf2 inhibitor TRG, HO-1 inhibitor ZnPP or GCL inhibitor BSO at non-toxic concentrations, confirming that the anti-oxidant and anti-inflammatory activity of 6a is related to the activation of Nrf2 signaling pathway. These results, together with the relatively safety profile, indicated that compound 6a could be a promising lead to develop novel anti-oxidant and anti-inflammatory agents, thus preventing diseases induced by oxidative stress and inflammation.


Assuntos
Acrilamida/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Acrilamida/síntese química , Acrilamida/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 176: 41-49, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091479

RESUMO

Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC50 values of 1.54 µM and 0.71 µM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284-1405, suggesting 5f possessed relatively safety profile than K284-1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC50 values of 1.90 and 0.84 µM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284-1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Quinazolinonas/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Sítios de Ligação , Replicação do DNA/efeitos dos fármacos , Células Hep G2 , Antígenos do Núcleo do Vírus da Hepatite B/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/toxicidade , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 162: 59-69, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30408749

RESUMO

Oxidative stress plays a significant role in the pathogenesis of various human diseases. In this study, a series of bifendate derivatives bearing acrylamide moiety were synthesized and evaluated as anti-oxidant agents. Biological evaluation indicated that compounds 6a and 6e displayed more potent cytoprotective effect against H2O2-induced HBZY-1 mesangial cells death than lead compound bifendate and positive control resveratrol and sulforaphane. Preliminary anti-oxidant mechanism studies showed that compound 6e could diminish the ROS accumulation by dose- and time-dependently activating Nrf2 and increasing the expression of downstream detoxification enzymes NQO-1, HO-1, GCLM and GCLC at protein and mRNA levels, thus displaying potent anti-oxidant activity. Interestingly, the Nrf2 activating effect of 6e is achieved, at least partly, in Michael acceptor and Keap1-dependent manners. These results, together with the low intrinsic cytotoxicity, suggested that compound 6e might be a promising lead for the development of novel anti-oxidant agents to prevent diseases induced by oxidative stress.


Assuntos
Acrilamida/química , Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Células Mesangiais/efeitos dos fármacos , Antioxidantes/química , Compostos de Bifenilo/síntese química , Humanos , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio , Relação Estrutura-Atividade
7.
Medchemcomm ; 9(11): 1826-1830, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30542532

RESUMO

Multidrug resistance (MDR) and metastasis are major causes of mortality in patients with cancer. We recently reported a bifendate derivative bearing a dibenzo[c,e]azepine scaffold (4i) as a P-gp and BCRP-medicated MDR reversal agent. As a continuation of the previous research, its ability to inhibit cancer metastasis was investigated in MDA-MB-231 cells in the present work. Wound-healing and chamber migration assays showed that 4i could significantly attenuate the migration of MDA-MB-231 cells. Additionally, 4i obviously suppressed the invasive activity of MDA-MB-231 cells, thus displaying potential anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 4i was associated with the inhibitory effect on the activity and expression of MMP-2 and MMP-9. These results, together with the previous findings, suggest that compound 4i could be a promising lead for the development of novel anti-cancer agents with anti-MDR and metastatic activities.

8.
Eur J Med Chem ; 145: 379-388, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29335204

RESUMO

As a continuation of previous research, fifteen bifendate derivatives bearing 6,7-dihydro-dibenzo [c,e]azepine scaffold were synthesized and evaluated as P-gp-medicated multidrug resistance (MDR) reversal agents. Biological evaluation indicated that compounds 6k and 9c more potently reversed P-gp-mediated MDR than bifendate and verapamil (VRP) by blocking P-gp mediated drug efflux function and not by decreasing P-gp expression in K562/A02 MDR cells. Interestingly, wound-healing and chamber migration assay showed that 6k and 9c could significantly attenuate the migration of MDA-MB-231 cells. Notably, 6k and 9c could markedly suppress the invasive activity of MDA-MB-231 cells, thus displayed potential anti-metastasis activity. Preliminary mechanism studies indicated that the anti-metastasis activity of 6k and 9c was associated with their inhibitory effect on the activity and expression of MMP-2 and MMP-9. These results, together with the MDR reversal results indicated that compounds 6k and 9c might be promising leads for developing novel anti-cancer agents with P-gp and tumor metastasis inhibitory activities.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Azepinas/farmacologia , Compostos de Bifenilo/farmacologia , Neoplasias/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Azepinas/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 144: 424-434, 2018 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-29288943

RESUMO

As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 µM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 µM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Desenho de Drogas , Vírus da Hepatite B/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
10.
J Med Chem ; 60(3): 928-940, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28068095

RESUMO

Multidrug resistance is a major obstacle to successful chemotherapy for leukemia. In this study, a series of nitric oxide (NO)-releasing bifendate derivatives (7a-n) were synthesized. Biological evaluation indicated that the most active compound (7a) produced relatively high levels of NO and significantly inhibited the proliferation of drug-resistant K562/A02 cells in vitro and in vivo. In addition, 7a induced the mitochondrial tyrosine nitration and the intracellular accumulation of rhodamine 123 by inhibiting P-gp activity in K562/A02 cells. Furthermore, 7a remarkably down-regulated AKT, NF-κB, and ERK activation and HIF-1α expression in K562/A02 cells, which are associated with the tumor cell proliferation and drug resistance. Notably, the antitumor effects were dramatically attenuated by an NO scavenger or elimination of the NO-releasing capability of 7a, indicating that NO produced by 7a contributed to, at least partly, its cytotoxicity against drug-resistant K562/A02 cells. Overall, 7a may be a potential agent against drug-resistant myelogenous leukemia.


Assuntos
Compostos de Bifenilo/farmacologia , Óxido Nítrico/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Xenoenxertos , Humanos , Técnicas In Vitro , Células K562 , Camundongos , Camundongos Nus
11.
Arch Pharm Res ; 40(7): 796-806, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28110416

RESUMO

Herein, a series of lasiokaurin derivatives were designed and synthesized. All the derivatives together with lasiokaurin and oridonin were tested for their antimicrobial and antiproliferative activity. Compound 16 showed the most promising antimicrobial activity with MICs of 2.0 and 1.0 µg/mL against Gram-Positive bacteria S. aureus and B. subtilis, respectively. All the synthetic lasiokaurin derivatives showed better antiproliferative activity than parent compound lasiokaurin 1. Compound 10 exhibited the strongest cytotoxicity with IC50 values of 0.47 and 0.20 µM against MGC-803 and CaEs-17 cells, accordingly. Moreover, it was shown to have potent antitumor activity in vivo in a murine model of MGC-803 gastric cancer. Preliminary SARs were also concluded based on obtained data. The apoptosis-inducing effects of 10 were further investigated using CaEs-17 cells. The results showed that lasiokaurin derivative 10 could induce apoptosis via mitochondria related pathway and arrest CaEs-17 cell cycle at S phase. Compound 10 could also affect apoptosis-related proteins that was up-regulation of CDK2 and down-regulation of ATM and cyclin A1.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/química , Diterpenos de Caurano/farmacologia , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Regulação para Cima/efeitos dos fármacos
12.
Int J Mol Sci ; 17(9)2016 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-27563888

RESUMO

Oridonin belongs to ent-kaurane tetracyclic diterpenoid and was first isolated from Isodon species. It exhibits inhibitory activities against a variety of tumor cells, and pharmacological study shows that oridonin could inhibit cell proliferation, DNA, RNA and protein synthesis of cancer cells, induce apoptosis and exhibit an antimutagenic effect. In addition, the large amount of the commercially-available supply is also very important for the natural lead oridonin. Moreover, the good stability, suitable molecular weight and drug-like property guarantee its further generation of a natural-like compound library. Oridonin has become the hot molecule in recent years, and from the year 2010, more than 200 publications can be found. In this review, we summarize the synthetic medicinal chemistry work of oridonin from the first publication 40 years ago and share our research experience of oridonin for about 10 years, which may provide useful information to those who are interested in this research field.


Assuntos
Diterpenos de Caurano/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química
13.
Chem Biodivers ; 13(11): 1584-1592, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27451105

RESUMO

A series of Matijin-Su (MTS, (2S)-2-{[(2S)-2-benzamido-3-phenylpropanoyl]amino}-3-phenylpropyl acetate) derivatives were synthesized and evaluated for their anti-HBV and cytotoxic activities in vitro. Six compounds (4g, 4j, 5c, 5g, 5h and 5i) showed significant inhibition against HBV DNA replication with the IC50 values in range of 2.18 - 8.55 µm, which were much lower than that of positive control lamivudine (IC50 82.42 µm). In particular, compounds 5h (IC50 2.18 µm; SI 151.59) and 5j (IC50 5.65 µm; SI 51.16) displayed relatively low cytotoxicities, resulting in high SI values. Notably, besides the anti-HBV DNA replication activity, compound 4j also exhibited more potent in vitro cytotoxic activity than 5-fluorouracil in two hepatocellular carcinoma cell (HCC) lines (QGY-7701 and SMMC-7721), indicating that 4j may be a promising lead for the exploration of drugs with dual therapeutic effects on HBV infection and HBV-induced HCC.


Assuntos
Antineoplásicos/farmacologia , Antivirais/farmacologia , Dipeptídeos/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dipeptídeos/síntese química , Dipeptídeos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 123: 21-30, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27474920

RESUMO

Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction. We assessed the ability of the prepared calix [n]arene polyhydroxyamine derivatives to induce cytotoxicity in six cancer cell lines by performing cancer cell growth inhibition assays. Results demonstrated that compounds 3a-3d achieved IC50 values ranging from 1.6 µM to 11.3 µM. Among the different compounds, 3a and 3b exerted the strongest cytotoxic effect in inhibiting the growth of SKOV3 cells. In relation to the underlying mechanisms of cytotoxic effects, cell cycle analysis revealed that the exposure of SKOV3 cells to 3a induced cell cycle arrest in the G0/G1 phase, suggesting a reduction in DNA synthesis. Immunofluorescent staining indicated that the protein expression levels of caspase-3 and p53 in cells significantly increased, whereas that of Bcl-2 was effectively suppressed. Meanwhile, no significant changes in Bax were observed in SKOV3 cells. These results highlight that calixarene 3a can be further studied as a potential anticancer agent.


Assuntos
Antineoplásicos/química , Calixarenos/química , Animais , Antineoplásicos/farmacologia , Calixarenos/síntese química , Calixarenos/farmacologia , Caspase 3/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Citostáticos/síntese química , Citostáticos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/efeitos dos fármacos
15.
J Cell Mol Med ; 20(6): 1095-105, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26864945

RESUMO

The development of multidrug resistance (MDR) not only actively transports a wide range of cytotoxic drugs across drug transporters but is also a complex interaction between a number of important cellular signalling pathways. Nitric oxide donors appear to be a new class of anticancer therapeutics for satisfying all the above conditions. Previously, we reported furoxan-based nitric oxide-releasing compounds that exhibited selective antitumour activity in vitro and in vivo. Herein, we demonstrate that bifendate (DDB)-nitric oxide, a synthetic furoxan-based nitric oxide-releasing derivative of bifendate, effectively inhibits the both sensitive and MDR tumour cell viability at a comparatively low concentration. Interestingly, the potency of DDB-nitric oxide is the independent of inhibition of the functions and expressions of three major ABC transporters. The mechanism of DDB-nitric oxide appears to be in two modes of actions by inducing mitochondrial tyrosine nitration and apoptosis, as well as by down-regulating HIF-1α expression and protein kinase B (AKT), extracellular signal-regulated kinases (ERK), nuclear factor κB (NF-κB) activation in MDR cells. Moreover, the addition of a typical nitric oxide scavenger significantly attenuated all the effects of DDB-nitric oxide, indicating that the cytotoxicity of DDB-nitric oxide is as a result of higher levels of nitric oxide release in MDR cancer cells. Given that acquired MDR to nitric oxide donors is reportedly difficult to achieve and genetically unstable, compound like DDB-nitric oxide may be a new type of therapeutic agent for the treatment of MDR tumours.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células K562 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
16.
Nutr Cancer ; 67(7): 1191-200, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26359917

RESUMO

Matrix metalloproteinases (MMPs) play an active role in facilitating the invasion of cancer cells with excessive extracellular matrix (ECM) degradation. In the present study, we investigated the antiinvasive effects of isorhamnetin, a naturally occurring flavonoid, on MDA-MB-231 human breast carcinoma cells. The results indicated that isorhamnetin significantly inhibited the adhesion, migration, and invasion of the cells in vitro. Moreover, isorhamnetin suppressed the activity and expression of MMP-2 and MMP-9, which were determined by gelatin zymography, real-time PCR, and Western blot analysis, respectively. Besides, isorhamnetin had little effect on the secretion of urokinase plasminogen activator. Further elucidation of the mechanism revealed that isorhamnetin exerted an inhibitory effect on the phosphorylation of p38 and STAT3, although it had no effect on ERK1/2 and JNK. Taken together, these data demonstrated that isorhamnetin could significantly inhibit the invasion of MDA-MB-231 cells by downregulating the expression and activity of MMP-2 and MMP-9, which was potentially associated with the suppression of p38 MAPK and STAT3. Therefore, the findings provide new evidence for the anti-cancer activity of isorhamnetin.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Quercetina/análogos & derivados , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/farmacologia , Quercetina/farmacologia , Fator de Transcrição STAT3/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Biochem Biophys Res Commun ; 455(3-4): 318-22, 2014 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-25446092

RESUMO

We previously described bifendate-chalcone hybrids as potent P-glycoprotein inhibitors. In the present work, we determine whether these compounds could reverse breast cancer resistance protein (BCRP, ABCG2)-mediated multidrug resistance using HEK293/BCRP cells which was BCRP-transfected stable HEK293 cells. Results indicated that compounds 8d, 8f, 8g and 8h could significantly enhance mitoxantrone accumulation in HEK293/BCRP cells via inhibiting BCRP drug efflux function. The most active compound 8g exhibited little intrinsic cytotoxicity (IC50>100 µM), and could reverse BCRP-mediated drug resistance independent of decreasing BCRP expression level. Notably, 8g had little inhibitory effect on multidrug resistance-associated protein 1 (MRP1, ABCC1), another drug efflux transporter. The present findings, together with the previous results, suggest that 8g might be act as dual inhibitors of P-gp and BCRP.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/química , Compostos de Bifenilo/química , Chalcona/administração & dosagem , Chalcona/química , Proteínas de Neoplasias/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/química , Química Farmacêutica , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Concentração Inibidora 50 , Proteínas de Neoplasias/química
18.
Bioorg Med Chem Lett ; 24(15): 3419-21, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24928398

RESUMO

We recently reported alkoxyl biphenyl derivatives bearing dibenzo[c,e]azepine scaffold as novel P-glycoprotein (P-gp, ABCB1) inhibitors. In this study, their ability to reverse breast cancer resistance protein (BCRP, ABCG2)-mediated multidrug resistance was tested in HEK293/BCRP cells which was BCRP-transfected stable HEK293 cells. It was observed that compounds 4d, 4h, 4i increased mitoxantrone accumulation in HEK293/BCRP cells via inhibiting BCRP efflux function. Notably, the inhibitory activity of 4i was comparable to that of the classical BCRP inhibitor Ko143 at an equimolar concentration. Interestingly, 4i had little inhibitory effect on multidrug resistance-associated protein 1 (MRP1, ABCC1), another drug efflux transporter. These results, together with the previous findings, suggest that 4i may be a dual inhibitor of P-gp and BCRP to warrant further investigation.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Compostos de Bifenilo/farmacologia , Clozapina/química , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Estrutura Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 51: 137-44, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22405646

RESUMO

Overexpression of P-glycoprotein (P-gp) is one of the major problems in successful treatment of cancers. To find new P-gp inhibitors, a series of bifendate (DDB) derivatives bearing dibenzo[c,e]azepine scaffold were synthesized and evaluated. Compound 4i more potently reversed P-gp-mediated multidrug resistance (MDR) than DDB and verapamil (VRP) by blocking P-gp mediated drug efflux function and increasing drug accumulation in K562/A02 MDR cells, and persisted longer chemo-sensitizing effect (>24 h) than VRP (<6 h). Interestingly, unlike VRP, 4i showed no stimulation on the P-gp ATPase activity, suggesting it is not a substrate of P-gp. Given the low intrinsic cytotoxicity of 4i in vitro, it may represent a promising lead for developing therapeutics targeting P-gp-mediated MDR in combinational cancer chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Azepinas/química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/metabolismo , Antineoplásicos/síntese química , Compostos de Bifenilo/síntese química , Técnicas de Química Sintética , Doxorrubicina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rodamina 123/metabolismo , Relação Estrutura-Atividade
20.
Bioorg Med Chem ; 20(8): 2540-8, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22429509

RESUMO

Overexpression of P-glycoprotein (P-gp) is one of the major problems to successful cancer chemotherapy. To find novel effective P-gp inhibitors, a series of bifendate-chalcone hybrids were synthesized and evaluated. Among them, the most active compound 8g had little intrinsic cytotoxicity (IC(50)>200 µM), and could increase accumulation of Rhodamine 123 in K562/A02 cells more potently than bifendate and verapamil (VRP) by inhibiting P-gp efflux function. And 8g displayed potent chemo-sensitizing effect and persisted for much longer time (>24h) compared with VRP (<6h). In addition, 8g, unlike VRP, showed no stimulation on the P-gp ATPase activity, suggesting it is not a P-gp substrate. Therefore, 8g may represent a promising lead to develop MDR reversal agents for cancer chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Chalcona/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA