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1.
Anticancer Res ; 39(9): 4749-4755, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519575

RESUMO

BACKGROUND: Cisplatin is a platinum compound capable of inducing apoptosis of cancer cells. However, cancer cells can become cisplatin-resistant. A recent study showed that a pregnane X receptor (PXR) antagonist, leflunomide, can enhance the antitumor activity of cisplatin and overcome such resistance. This study determined whether PXR antagonists ketoconazole and phenethyl isothiocyanate (PEITC) enhance the antitumor activity of platinum compounds and by which mechanism(s) of action. MATERIALS AND METHODS: Caspase-3 activity, intracellular platinum level, and expression of ATP-binding cassette subfamily C member 2 (ABCC2; previously named multidrug resistance-associated protein 2) were assessed in HepG2 human hepatocellular carcinoma cells exposed to carboplatin or cisplatin with and without PXR antagonist. RESULTS: In combination with platinum compounds, PEITC increased the intracellular platinum level, while ketoconazole induced higher caspase-3 activity. Additionally, PEITC suppressed ABCC2 protein expression. CONCLUSION: These results suggested that ketoconazole and PEITC enhance the antitumor activity of platinum compounds by different and complex mechanisms.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Receptor de Pregnano X/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Biomarcadores , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , RNA Mensageiro/genética
2.
Anticancer Res ; 39(9): 4757-4766, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519576

RESUMO

BACKGROUND/AIM: Azacitidine (AZA) is a hypomethylating agent used in myeloid neoplasms, however, approximately half of patients show treatment failure or relapse. This in vitro study investigated the effect of the combination of AZA with the natural compound curcumin (CUR) in increasing its efficacy. MATERIALS AND METHODS: We analyzed the effects of AZA plus CUR on proliferation, apoptosis, cell cycle and differentiation in myeloid leukemic cell lines (U-937, HL-60, K-562, and OCI-AML3) and bone marrow samples of patients. RESULTS: The results showed a synergy between AZA and CUR in all leukemic lines and in most leukemic samples, with a decrease in proliferation and an increase in apoptosis compared to the activity of each drug separately. In addition, AZA plus CUR showed low cytotoxicity in healthy samples. CONCLUSION: A remarkable antioncogenic effect of the combination of AZA plus CUR was shown, providing a basis for future studies analyzing the clinical efficacy of these drugs.


Assuntos
Antineoplásicos/farmacologia , Azacitidina/farmacologia , Curcumina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Mieloide/genética , Masculino , Síndromes Mielodisplásicas/genética
3.
Anticancer Res ; 39(9): 4987-4993, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519605

RESUMO

BACKGROUND/AIM: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment. PATIENTS AND METHODS: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history. RESULTS: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients. CONCLUSION: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Docetaxel/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
4.
J Med Microbiol ; 68(10): 1552-1559, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419210

RESUMO

Introductio n. Pseudomonas aeruginosa is an important Gram-negative pathogen that is intrinsically multidrug-resistant (MDR) and frequently associated with healthcare-associated outbreaks. With increasing resistance to antibiotics and with very few novel drugs under development, clinicians often use combinations to treat critically ill patients.Aim. The aim of this study was to evaluate the ability of epigallocatechin (EGCG) to restore the activity of aztreonam against clinical MDR strains of P. aeruginosa.Methodology. Checkerboard and time-kill kinetic assays were performed to assess synergy in vitro and the Galleria mellonella model of infection was used to test the efficacy of the combination in vivo. Accumulation assays were performed to gain insight into the mechanism of action.Results. The results demonstrate that synergy between aztreonam and EGCG exists [fractional inhibitory concentration indices (FICIs) 0.02-0.5], with the combination affording significantly (P=<0.05) enhanced bacterial killing, with a >3 log10 reduction in colony-forming units ml-1 at 24 h. EGCG was able to restore susceptibility to aztreonam to a level equal to or below the breakpoint set by the European Committee for Antimicrobial Susceptibility Testing. In G. mellonella, the combination was superior to monotherapy, with increased larval survival observed (94 % vs ≤63 %). We also demonstrated the relatively low toxicity of EGCG to human keratinocytes and G. mellonella larvae. Accumulation assay data suggest that the mechanism of synergy may be due to EGCG increasing the uptake of aztreonam.Conclusion. EGCG was able to restore the activity of aztreonam against MDR P. aeruginosa. The data presented support further evaluation of the aztreonam-EGCG combination and highlight its potential for use in clinical medicine.


Assuntos
Antibacterianos/farmacologia , Aztreonam/farmacologia , Catequina/análogos & derivados , Polifenóis/farmacologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Catequina/farmacologia , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Humanos , Larva/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mariposas/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento
5.
Pharm Res ; 36(10): 145, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396764

RESUMO

PURPOSE: The immediate plasma metabolism and development of chemo-resistance (single agent) severely hampers the clinical effectiveness of Sorafenib (SRF) in liver cancer therapy. MicroRNA27a inhibition is a promising biological strategy for breast cancer therapy. METHODS: In this study, we aimed to prepare SRF and anti-miRNA27a-loaded anti-GPC3 antibody targeted lipid nanoparticles to enhance the therapeutic efficacy against liver cancers. In this study, we have employed a unique cationic switchable lipid (CSL) as a mean to encapsulate miRNA as well as to confer pH-responsiveness to the nanocarrier system. RESULTS: The G-S27LN was nanosized and offered a pH-responsive release of SRF from the carrier system and we have demonstrated the specific affinity of G-S27LN towards the GPC3-overexpressed HepG2 cancer cells. Anti-microRNA27a significantly increased the protein expression of FOXO1 and PPAR-γ which are crucial components involved in proliferation and apoptosis of tumor cells. Combination of SRF and anti-miRNA27a (G-S27LN) resulted in significantly lower cell viability with a marked increase in the apoptosis cell proportion compared to that of free SRF indicating the synergistic anticancer effect. Animal studies in liver cancer xenograft model demonstrated significant suppression of tumor burden, reduced tumor cell and elevated TUNEL positive apoptosis with no toxicity concerns in animals treated with G-S27LN formulation. CONCLUSION: The CSL-based G-S27LN efficiently co-delivered anti-microRNA27a and SRF and therefore represents a promising therapy to treat liver cancer. This study also brings forth a platform strategy for the effective treatment of number of other advanced cancers.


Assuntos
Antagomirs/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glipicanas/imunologia , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/imunologia , Nanopartículas/química , Sorafenibe/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Sinergismo Farmacológico , Proteína Forkhead Box O1/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , PPAR gama/metabolismo , Fosforilcolina/química , Polietilenoglicóis/química
6.
Cancer Invest ; 37(7): 311-324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31412710

RESUMO

Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/genética , Purinas/farmacologia , Quinazolinonas/farmacologia , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
7.
Int J Nanomedicine ; 14: 4503-4515, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417255

RESUMO

Purpose: Drug resistance is a major challenge for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment of lung cancer. Ferumoxytol (FMT) drives macrophage (MΦ) transformation towards a M1-like phenotype and thereby inhibits tumor growth. CpG oligodeoxynucleotide 2395 (CpG), a toll-like receptor 9 (TLR9) agonist, is an effective therapeutic agent to induce anticancer immune responses. Herein, the effect of co-administered FMT and CpG on MΦ activation for treating non-small cell lung cancer (NSCLC) was explored. Methods: The mRNA expression levels of M1-like genes in RAW 264.7 MΦ cells stimulated by FMT, CpG and FMT and CpG (FMT/CpG) were evaluated by quantitative reverse transcription PCR (qRT-PCR). Then, the effects of FMT/CpG-pretreated MΦ supernatant on apoptosis and proliferation of H1975 cells were detected by flow cytometry, and the expression of EGFR and its downstream signaling pathway in H1975 cells were explored by western blotting. Finally, a H1975 cell xenograft mouse model was used to study the anti-tumor effect of the combination of FMT and CpG in vivo. Results: FMT and CpG synergistically enhanced M1-like gene expression in MΦ, including tumor necrosis factor-α, interleukin (IL)-12, IL-1α, IL-1ß, IL-6 and inducible nitric oxide synthase (iNOS). FMT/CpG-pretreated MΦ supernatant inhibited proliferation and induced apoptosis of H1975 cells, accompanied by down-regulation of cell cycle-associated proteins and up-regulation of apoptosis-related proteins. Further studies indicated that the FMT/CpG-pretreated MΦ supernatant suppressed p-EGFR and its downstream AKT/mammalian target of rapamycin signaling pathway in H1975 cells. Furthermore, FMT/CpG suppressed tumor growth in mice accompanied by a decline in the EGFR-positive tumor cell fraction and increased M1 phenotype macrophage infiltration. Conclusion: FMT acted synergistically with CpG to activate MΦ for suppressed proliferation and promoted apoptosis of NSCLC cells via EGFR signaling. Thus, combining FMT and CpG is an effective strategy for the treatment of NSCLC with EGFRL858R/T790M mutation.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Óxido Ferroso-Férrico/uso terapêutico , Macrófagos/metabolismo , Mutação/genética , Oligodesoxirribonucleotídeos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/genética , Feminino , Óxido Ferroso-Férrico/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Life Sci ; 233: 116709, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369760

RESUMO

BACKGROUND: Cisplatin resistance has been found to contribute to the failure of ovarian carcinoma treatment. Oridonin is a natural en-kaurane tetracyclic diterpenoid compound discovered in Rabdosia rubescene (Henmsl.) Hara. Herein, we tested whether oridonin could exert chemo-sensitization activity on cisplatin-resistant ovarian carcinoma cells. METHODS: Firstly, A2780CP cells and SKOV3/DDP cells were exposed to cisplatin and/or oridonin treatment. Cell counting kit-8 (CCK-8) kit and Dead Cell Apoptosis Kit with Annexin V-FITC and PI were carried out to test cell viability and apoptosis, respectively. Then, pBeclin-1 was transfected to overexpress Beclin-1. 3-Methyladenine (3-MA) acted as autophagy inhibitor, while rapamycin acted as autophagy activator. Finally, the influence of cisplatin and/or oridonin treatment on human normal ovarian epithelial IOSE 364 cell viability and apoptosis were also detected. RESULTS: Oridonin incubation notably elevated the cisplatin-caused reduction of A2780CP and SKOV3/DDP cell viabilities and enhancement of cell apoptosis. Cisplatin-caused A2780CP and SKOV3/DDP cell autophagy was dramatically inhibited by oridonin. Overexpression of Beclin-1 mitigated the influence of oridonin on cisplatin-caused A2780CP and SKOV3/DDP cell autophagy. Inhibition of cell autophagy by 3-MA promoted the oridonin + cisplatin-caused A2780CP and SKOV3/DDP cell apoptosis, while activation of cell autophagy by rapamycin had opposite effects. Oridonin and cisplatin co-treatment had no significant effects on IOSE 364 cell viability and apoptosis. CONCLUSION: The chemo-sensitization activity of oridonin on cisplatin-resistant ovarian carcinoma cells was verified in this study. Oridonin elevated sensitivity of ovarian carcinoma cells to cisplatin via suppressing cisplatin-mediated autophagy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Cisplatino/farmacologia , Diterpenos de Caurano/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Neoplasias Ovarianas/patologia , Antineoplásicos/farmacologia , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Células Tumorais Cultivadas
9.
J Med Microbiol ; 68(9): 1292-1298, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31361213

RESUMO

Introduction. Carbapenemase-producing Enterobacteriaceae have become a major public health concern over the last decade and treatment options are limited.Aims. We evaluated the synergistic activity of the combination of aztreonam (ATM) and clavulanate for 41 ß-lactam-resistant clinical isolates harbouring class B or/and class D carbapenemases combined or not with extended-spectrum ß-lactamases (ESBLs).Methodology. The MICs of ATM, with and without amoxicillin-clavulanate (AMC), were determined. Time-kill assays were performed for three representative strains.Results. The ATM-AMC combination had a synergistic effect on 34/41 (83 %) isolates. The MIC of ATM, in the presence of clavulanate, was ≤1 mg l-1 for 15/41 (37 %) isolates and ≤4 mg l-1 for 29/41 (71 %) isolates. Synergistic activity was observed for 34/37 (92 %) isolates producing ESBLs and carbapenemases, compared to 0/4 (0 %) for ESBL-negative strains. Complete or partial bactericidal activity was obtained when the MIC of the combination was 0.5 mg l-1 and 1.5 mg l-1 or 8 mg l-1, respectively.Conclusion. The combination of ATM and AMC could be an attractive unconventional treatment for infections due to carbapenemase- and ESBL-producing Enterobacteriaceae.


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/farmacologia , Aztreonam/farmacologia , Proteínas de Bactérias/metabolismo , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Sinergismo Farmacológico , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Enterobacteriáceas Resistentes a Carbapenêmicos/enzimologia , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Infecções por Enterobacteriaceae/microbiologia , Humanos , Testes de Sensibilidade Microbiana
10.
J Environ Sci Health B ; 54(7): 580-589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266377

RESUMO

This study aimed to compare the toxicity for fish of two active ingredients (lambda-cyhalothrin-20 g L-1, a pyrethroid, and acetamiprid-15 g L-1, a neonicotinoid) which are components of a commercial insecticide (Acer 35 EC) used in cotton crop in many West African countries. The juveniles of Oreochromis niloticus (4.01 ± 0.34 g, mean body weight) were exposed for 96 h to increasing concentrations of active ingredients (lambda-cyhalothrin and acetamiprid) or a mixture similar to Acer 35 EC (composed by 20 g of chemical compound lambda-cyhalothrin and 15 g of acetamiprid dissolved in 1 L of acetone). The experiments were carried out under controlled conditions in aquaria according to OECD Guidelines. During the experiments, the behavioral responses (loss of balance, color change, hyperactivity, etc.) that usually precede death were observed in exposed fish. Mortalities were recorded in each aquarium and the LC50-96h of each chemical was determined. The LC50-96h obtained were respectively 0.1268, 0.0029, 182.9 and 0.5685 ppm for Acer 35 EC, lambda-cyhalothrin, acetamiprid and mixture. All insecticides used in this study had profound impact on Nile tilapia behavior which may confirm the neurotoxicity of each single active compound as well as of their mixture.


Assuntos
Ciclídeos , Neonicotinoides/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Ciclídeos/fisiologia , Sinergismo Farmacológico , Inseticidas/toxicidade , Dose Letal Mediana , Mortalidade , Testes de Toxicidade Aguda , Poluentes Químicos da Água/toxicidade
11.
Life Sci ; 232: 116678, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344429

RESUMO

AIMS: In this work, it was sought to determine if there was synergism between doxorubicin (DOX), a well-known antineoplastic, and sclareol (SC), a diterpene from natural origin, in breast cancer treatment. Moreover, it was investigated if their co-loading in the same nanocarrier would result in a gain of activity and/or a toxicity diminishment. MAIN METHODS: The synergism of the DOX:SC combination was evaluated in MDA-MB-231 and 4T1 cells. A nanostructured lipid carrier (NLC) co-encapsulating DOX and SC in their synergistic molar ratio was prepared and characterised, in terms of mean diameter, zeta potential, DOX encapsulation efficiency, small angle X-ray scattering, differential scanning calorimetry, and polarised light microscopy for further intravenous administration. The anticancer activity of the combination, free and encapsulated, was evaluated in 4T1-tumour bearing mice. KEY FINDINGS: It was determined that DOX:SC combination at the molar ratio 1:1.9 presents better synergistic anticancer activity than the molar ratio 1:7.5 in vitro. DOX:SC-loaded NLC (NLC-DOX-SC) improved in vitro cytotoxic and in vivo antitumour activity compared to free DOX. Although NLC-DOX-SC and free DOX:SC, at the synergistic molar ratio, showed similar activity in the in vivo study, the free combination provoked body weight loss, behaviour alterations and haematological toxicity in the animals, while this was not observed for NLC-DOX-SC. SIGNIFICANCE: This work shows that SC and DOX present synergistic anticancer activity for breast cancer treatment whereas NLC-DOX-SC was a feasible alternative to attain the benefits posed by DOX:SC combination but with none to fewer side effects.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Diterpenos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos , Lipídeos/química , Nanoestruturas/química , Neoplasias de Mama Triplo Negativas/patologia , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C
12.
Planta Med ; 85(11-12): 997-1007, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288278

RESUMO

Silymarin-enriched extract (SEE) is obtained from Silybum marianum (Asteraceae). Doxorubicin (DXR) is a widely used chemotherapeutical yet with severe side effects. The goal of the present study was to assess the pharmacologic effect of SEE and its bioactive components silibinin and silychristine when administrated alone or in combination with DXR in the human prostate cancer cells (PC-3). PC-3 cells were treated with SEE, silibinin (silybins A and B), silychristine, alone, and in combination with DXR, and cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis, and autophagy rate were assessed by flow cytometry. Expression levels of autophagy-related genes were quantified by qRT-PCR, ELISA and western blot while transmission electron microscopy was performed to reveal autophagic structures. Finally, NMR spectrometry was used to identify specific metabolites related to autophagy. SEE inhibited PC-3 cell proliferation in a dose-dependent manner while the co-treatment (DXR-SEE) revealed an additive cytotoxic effect. Cell cycle, apoptosis, and autophagy variations were observed in addition to altered expression levels of autophagy related genes (LC3, p62, NBR1, Beclin1, ULK1, AMBRA1), while several modifications in autophagic structures were identified after DXR-SEE co-treatment. Furthermore, treated cells showed a different metabolic profile, with significant alterations in autophagy-related metabolites such as branched-chain amino acids. In conclusion, the DXR-SEE co-treatment provokes perturbations in the autophagic mechanism of prostate cancer cells (PC-3) compared to DXR treatment alone, causing an excessive cell death. These findings propose the putative use of SEE as an adjuvant cytotoxic agent.


Assuntos
Doxorrubicina/uso terapêutico , Cardo Mariano/química , Extratos Vegetais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Silimarina/uso terapêutico , Western Blotting , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Masculino , Células PC-3/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Silimarina/isolamento & purificação
13.
Chem Biol Interact ; 310: 108731, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31265827

RESUMO

Lung cancer is one of the most common and lethal types of oncological diseases. Despite the advanced therapeutic approaches, the prognosis for lung cancer still remains poor. Apparently, there is an imperative need for more efficient therapeutic strategies. In this work we report that concurrent treatment of human adenocarcinoma A549 cells with specific concentrations of two antitumor agents, the sphingosine kinase 1 inhibitor N, N dimethylsphingosine (DMS) and the alkylphosphocholine miltefosine, induced synergistic cytotoxic effect, which was confirmed by calculation of the combination index. The simultaneous action of these agents, induced significant decrease of A549 cell number, as well as pronounced morphological alterations. Combined drugs caused substantial apoptotic events, and significant reduction of the pro-survival marker sphingosine- 1-phosphate (S1P), when compared to the individual treatments with each of the anticancer drugs alone. Miltefosine is known to affect the synthesis of choline-containing phospholipids, including sphingomyelin, but we report for the first time that it also reduces S1P. Here we suggest a putative mechanism underlying the effect of miltefosine on sphingosine kinase 1, involving miltefosine-induced inhibition of protein kinase C. In conclusion, our findings provide a possibility for treatment of lung cancer cells with lower concentrations of the two antitumor drugs, DMS and miltefosine, which is favorable, regarding their potential cytotoxicity to normal cells.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Apoptose/efeitos dos fármacos , Fosforilcolina/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica , Sinergismo Farmacológico , Humanos , Lisofosfolipídeos/análise , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Esfingosina/análogos & derivados , Esfingosina/análise
14.
Chem Biol Interact ; 310: 108740, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31288002

RESUMO

BACKGROUND: Solid Ehrlich Carcinoma (SEC) is an undifferentiated tumor used in tumor studies and chemotherapy investigations. AIM: to assess the anti-tumor potential of luteolin when used either alone or combined to 5-fluorouracil (5-FU) against SEC. METHOD: SEC was induced in 40 female mice; they were categorized into 4 equal groups; group I (untreated SEC), group II (5-FU treated SEC), group III (luteolin treated SEC) and group IV (5-FU + luteolin treated SEC). Tumor volume and weight were calculated. P53, p21, caspase 3 and damage regulated autophagy modulator (DRAM) were assessed. Biomarkers of oxidant/antioxidant status in addition to immunohistochemistry for cylin D1 were evaluated. RESULTS: combined administration of luteolin and 5-FU in SEC model increased levels of p53, p21, caspase 3, DRAM and survivability while, tumor volume, weight, thioredoxin reductase one (TR1) activity and cyclin D1 expression showed the reverse with restoration of oxidant/antioxidant indices. CONCLUSION: current results proved the antitumor therapeutic effects of luteolin alone or combined with 5-FU as a novel strategy for cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Ehrlich/tratamento farmacológico , Fluoruracila/farmacologia , Luteolina/farmacologia , Animais , Caspase 3/efeitos dos fármacos , Sinergismo Farmacológico , Fluoruracila/uso terapêutico , Luteolina/uso terapêutico , Camundongos , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos
15.
Gene ; 712: 143959, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278964

RESUMO

Blockade of Hedgehog signaling can prevent osteoarthritis (OA) syndromes. However, the amelioration of related inflammation condition is limited. The purpose of this study was to observe the effect of combined use of Hedgehog signaling inhibitor GANT-61 and common clinical anti-inflammatory drug indomethacin on cartilage injury and inflammation in experimental OA mice. We found that GANT-61 and indomethacin synergistically attenuate cartilage damage and serum levels of inflammatory cytokines TNF-α, IL-2 and IL-6 in OA mice. Moreover, in vitro treatment of GANT-61 and indomethacin synergistically reduced the mRNA expression of TNF-α, IL-2 and IL-6 in lipopolysaccharide (LPS)-stimulated C28/I2 chondrocytes. Mechasnistic studies showed that GANT-61 and indomethacin synergistically attenuate the expressions of cell pyroptosis-related genes caspase-1, IL-1ß and IL-18 at mRNA and protein level. To conclude, our study showed that GANT-61 and indomethacin had a synergistically ameliorating effect on osteoarthritis by mediating chondrocytes pyroptosis.


Assuntos
Cartilagem/efeitos dos fármacos , Condrócitos/citologia , Proteínas Hedgehog/antagonistas & inibidores , Indometacina/farmacologia , Osteoartrite/tratamento farmacológico , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Cartilagem/patologia , Caspase 1/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piroptose , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
16.
Gene ; 712: 143966, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279711

RESUMO

BACKGROUND: Acute paracetamol (PCM) toxicity is a clinical problem; can result in a serious liver injury that finally may progress to acute liver failure. Curcumin (CUR) is a prevalent natural compound that can maintain prooxidant/antioxidant balance and thus can help in liver protection; also, Silymarin (SL) is a traditional antioxidant herb, used to treat liver disorders through scavenging free radicals. This study aimed to illustrate the histological, biochemical and molecular changes induced by acute PCM overdose on rats' liver to elucidate the effectiveness of CUR compared to SL in alleviating such changes. MATERIALS AND METHODS: Male Wister Albino rats were divided into 6 groups each comprising 23 rats: control group, curcumin (CUR) treated group received (100 mg CUR/ kg), silymarin treated group received (100 mg SL/kg) for 7 successive days. Paracetamol (PCM) exposed group administered a single dose of PCM (200 mg/kg orally on 8th day). PCM + CUR group and PCM + SL group pretreated with CUR and SL respectively for 7 days then received single PCM dose (200 mg/kg) on the 8th day. Blood and liver tissues were collected for biochemical, histopathological and immunohistochemical analyses using anti-p53 antibody. In addition, real time polymerase chain reaction (RT- PCR) was used to measure Bax, bcl2 and Peroxisome proliferator-activated receptor-gamma (PPAR γ) mRNA expression levels. RESULTS: In the paracetamol overdose group, the liver architecture showed necrotic changes, hydropic degeneration, congestion and dilatation of central veins. This hepatocellular damage was confirmed by a significant increase of AST, ALT levels and by an apparent increase in the number of p53 stained cells. PCM toxicity showed significant elevation of total oxidant status (TOS), oxidant status index (OSI) and decreased total antioxidant capacity (TAC) compared to controls (p < 0.001). Gene expression analysis showed that PCM caused an elevation of bcl2 and a reduction of both Bax and PPARγ mRNA expression. The histological alternation in the liver architecture was markedly improved in (PCM + CUR) group compared to (PCM+ SL) group, with an obvious decrease in the number of P53 stained cells. CUR pretreatment inhibited the elevation of TOS and OSI as well as the reduction of TAC caused by PCM toxicity compared to (PCM + SL) group. CONCLUSION: Both SL and CUR pretreatment prevented the toxic effects of PCM, but CUR is more effective than SL in ameliorating acute PCM induced hepatotoxicity.


Assuntos
Acetaminofen/toxicidade , Curcumina/farmacologia , Falência Hepática Aguda/induzido quimicamente , Fígado/efeitos dos fármacos , Silimarina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Apoptose , Sinergismo Farmacológico , Imuno-Histoquímica , Masculino , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Proteína X Associada a bcl-2/metabolismo
17.
Cell Physiol Biochem ; 53(2): 285-300, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31334617

RESUMO

BACKGROUND/AIMS: Although naturally-derived antifungals have been investigated for their ability to inactivate Candida albicans, which is a major cause of candidiasis, they have shown a less than 3 log reduction in C. albicans or required treatment times of longer than 3 h. Thus, the naturally-derived antifungals used in previous studies could not substantially eradicate C. albicans within a short period of time. METHODS: To improve the fungicidal effects of naturallyderived antifungals against C. albicans within short time periods, we developed composites showing antifungal synergism using caprylic acid (CA), carvacrol (CAR) and thymol (THM) for 1-10 min at 22/37°C. Using flow cytometry, we examined the mode of action for the synergism of these compounds on membrane integrity and efflux pump activity. RESULTS: Whereas the maximum reduction by individual treatments was 0.6 log CFU/ml, CA + CAR/THM (all 1.5 mM) eliminated all pathogens (> 6.8 log reduction) after 1 min at 37°C and after 10 min at 22°C. The flow cytometry results showed that exposure to CA damaged the membranes in 15.7-36.5% of cells and inhibited efflux pumps in 15.4-31.3% of cells. Treatments with CAR/THM slightly affected cell membranes (in 1.8-6.9% of cells) but damaged efflux pumps in 14.4-29.6% of cells. However, the combined treatments clearly disrupted membranes (> 83.1% of cells) and pumps (> 95.0% of cells). The mechanism of this synergism may involve membrane damage by CA, which facilitates the entry of antifungals into the cytoplasm, and the inhibition of efflux pumps by CA, CAR or THM, causing their accumulation within cells and, leading to cell death. CONCLUSION: Antifungal composites (CA + CAR/THM) showing synergism (i.e., an additional 6 log reduction) within minutes at room/body temperature can be used to treat candidiasis and improve the microbiological safety of facilities contaminated with fungi as a novel alternative to synthetic antifungals.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Caprilatos/farmacologia , Proteínas Fúngicas/metabolismo , Monoterpenos/farmacologia , Timol/farmacologia , Candida albicans/metabolismo , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Sinergismo Farmacológico , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Temperatura Ambiente
18.
J Sci Food Agric ; 99(14): 6562-6571, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31321778

RESUMO

BACKGROUND: Excessive reactive oxygen species (ROS) may attack biological macromolecules and induce oxidative stress. The inhibition by ascorbic acid (AsA) on oxidative damage has been reported in fruits, while the barrier effect of ceramide has also been proven. However, there are few reports about the effects of ceramide-AsA interactions to enhance storability and boost antioxidant systems in fruits during storage. This study was conducted to study the synergistic effects of AsA in combination with ceramide on the quality of postharvest strawberry (Fragaria anannasa cv. Tianbao). RESULTS: Treatment with 100 mg L-1 AsA plus 1.2 mmol L-1 ceramide significantly delayed the rot of strawberries, reduced the water loss and the contents of ROS, malonaldehyde (MDA), and proline, however, increased the contents of total flavonoids, total phenols, and anthocyanins compared with other treatments. Also, treatment with 100 mg L-1 AsA plus 1.2 mmol L-1 ceramide significantly increased the activities of peroxidase (POD) and superoxide dismutase (SOD) but inhibited the activity of polyphenol oxidase (PPO). CONCLUSION: It is suggested that treatment with 100 mg L-1 AsA plus 1.2 mmol L-1 ceramide could significantly reduce the oxidative damage and maintain the storage quality of strawberries during storage by enhancing the antioxidant systems. © 2019 Society of Chemical Industry.


Assuntos
Antioxidantes/metabolismo , Ácido Ascórbico/farmacologia , Ceramidas/farmacologia , Conservação de Alimentos/métodos , Conservantes de Alimentos/farmacologia , Fragaria/efeitos dos fármacos , Catalase/metabolismo , Sinergismo Farmacológico , Armazenamento de Alimentos , Fragaria/química , Fragaria/metabolismo , Frutas/química , Frutas/efeitos dos fármacos , Frutas/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
19.
Anticancer Res ; 39(7): 3531-3542, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262877

RESUMO

BACKGROUND/AIM: Recently, we demonstrated the ability of inhibitors of protein kinase 2 (casein kinase II; CK2) to enhance the efficacy of 5-fluorouracil, a thymidylate synthase (TYMS)-directed drug for anticancer treatment. The present study aimed to investigate the antileukemic effect of simultaneous inhibition of dihydrofolate reductase (DHFR), another enzyme involved in the thymidylate biosynthesis cycle, and CK2 in CCRF-CEM acute lymphoblastic leukemia cells. MATERIALS AND METHODS: The influence of combined treatment on apoptosis and cell-cycle progression, as well as the endocellular level of DHFR protein and inhibition of CK2 were determined using flow cytometry and western blot analysis, respectively. Real-time quantitative polymerase chain reaction was used to examine the influence of silmitasertib (CX-4945), a selective inhibitor of CK2 on the expression of DHFR and TYMS genes. RESULTS: The synergistic effect was correlated with the increase of annexin V-binding cell fraction, caspase 3/7 activation and a significant reduce in the activity of CK2. An increase of DHFR protein level was observed in CCRF-CEM cells after CX-4945 treatment, with the mRNA level remaining relatively constant. CONCLUSION: The obtained results demonstrate a possibility to improve methotrexate-based anti-leukemia therapy by simultaneous inhibition of CK2. The effect of CK2 inhibition on DHFR expression suggests the important regulatory role of CK2-mediated phosphorylation of DHFR inside cells.


Assuntos
Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Metotrexato/farmacologia , Naftiridinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Tetra-Hidrofolato Desidrogenase/metabolismo
20.
Anticancer Res ; 39(7): 3579-3584, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262882

RESUMO

BACKGROUND/AIM: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood; treatments with greater effectiveness are required for NB, especially in advanced cases. This study aimed at evaluating the combined effect of anaplastic lymphoma kinase (ALK) inhibitor alectinib and histone deacetylase inhibitor vorinostat on NB cell lines harboring wild-type or mutated ALK. MATERIALS AND METHODS: Cytotoxicity was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression was analyzed using western blotting. RESULTS: Combination treatment with alectinib and vorinostat had a synergistic effect on growth inhibition of the NB cell line with ALK R1275Q mutation. Cleavage of caspase-3 and poly-(ADP-ribose) polymerase increased, indicating enhanced caspase-dependent apoptosis. In addition, this combination reduced the protein levels of MYCN proto-oncogene and nuclear factor kappa B, both of which are important for NB tumorigenesis and progression. CONCLUSION: Combined treatment with alectinib and vorinostat might be a novel therapeutic option for NB harboring the ALK R1275Q mutation.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Neuroblastoma/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Vorinostat/farmacologia , Quinase do Linfoma Anaplásico/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Mutação , Proteína Proto-Oncogênica N-Myc/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo
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