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1.
Toxicol Appl Pharmacol ; 329: 272-281, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28610991

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Triterpenos/farmacologia , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/toxicidade , Compostos Radiofarmacêuticos/administração & dosagem , Fatores de Tempo , Testes de Toxicidade Subcrônica , Triterpenos/toxicidade , Carga Tumoral/efeitos dos fármacos , Imagem Corporal Total , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Chem Res Toxicol ; 28(10): 1949-60, 2015 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-26372186

RESUMO

Nonsmall cell lung cancer (NSCLC) represents an important cause of mortality worldwide due to its aggressiveness and growing resistance to currently available therapy. Cucurbitacins have emerged as novel potential anticancer agents showing strong antiproliferative effects and can be promising candidates for combined treatments with clinically used anticancer agents. This study investigates the synergistic antiproliferative effects of a new semisynthetic derivative of cucurbitacin B (DACE) with three chemotherapy drugs: cisplatin (CIS), irinotecan (IRI), and paclitaxel (PAC) on A549 cells. The most effective combinations were selected for studies of the mechanism of action. Using an in silico tool, DACE seems to act by a different mechanism of action when compared with that of different classes of drugs already used in clinical settings. DACE also showed potent synergic effects with drugs, and the most potent combinations induced G2/M cell cycle arrest by modulating survivin and p53 expression, disruption of F-actin cytoskeleton, and cell death by apoptosis. These treatments completely inhibited the clonogenic potential and did not reduce the proliferation of nontumoral lung cells (MRC-5). DACE also showed relevant antimigratory and anti-invasive effects, and combined treatments modulated cell migration signaling pathways evolved with metastasis progression. The effects of DACE associated with drugs was potentiated by the oxidant agent l-buthionine-sulfoximine (BSO), and attenuated by N-acetilcysteine (NAC), an antioxidant agent. The antiproliferative effects induced by combined treatments were attenuated by a pan-caspase inhibitor, indicating that the effects of these treatments are dependent on caspase activity. Our data highlight the therapeutic potential of DACE used in combination with known chemotherapy drugs and offer important insights for the development of more effective and selective therapies against lung cancer.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Triterpenos/farmacologia , Actinas/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Irinotecano , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Survivina , Triterpenos/química , Triterpenos/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo
3.
Mar Drugs ; 12(12): 5864-80, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25486111

RESUMO

Five new polyoxygenated marine steroids-punicinols A-E (1-5)-were isolated from the gorgonian Leptogorgia punicea and characterized by spectroscopic methods (IR, MS, 1H, 13C and 2-D NMR). The five compounds induced in vitro cytotoxic effects against lung cancer A549 cells, while punicinols A and B were the most active, with IC50 values of 9.7 µM and 9.6 µM, respectively. The synergistic effects of these compounds with paclitaxel, as well as their effects on cell cycle distribution and their performance in the clonogenic assay, were also evaluated. Both compounds demonstrated significant synergistic effects with paclitaxel.


Assuntos
Antozoários/química , Esteroides/química , Esteroides/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Espectroscopia de Ressonância Magnética/métodos , Paclitaxel/farmacologia
4.
DNA Cell Biol ; 32(2): 58-65, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23323927

RESUMO

Mesenchymal stem cells (MSCs) are multipotent stem cells with clinical interest. It has been reported that MSCs can be isolated from the human term placenta. We investigated the ability of human placenta-derived MSCs to differentiate into a neural phenotype in coculture assays with astrocytes obtained from neonatal rats. Placenta-derived MSCs were cocultured on a confluent monolayer of astrocytes obtained from the rat cerebellum to evaluate the differences in morphology. The extracellular matrix (ECM) produced by astrocytes as well as the growth factors produced by the astrocyte-conditioned medium were evaluated. The expression of the neural markers glial fibrillate acid protein (GFAP) and Nestin was studied in MSCs by immunocytochemistry. MSCs were able to respond to the astrocyte niche in coculture assays. They expressed the neural markers GFAP, Nestin, or ß-Tubulin III, followed by an outgrowth of cell processes. The ECM from astrocytes was not effective in inducing the neural phenotype in MSCs, although the expression of ß-Tubulin III was observed. When MSCs were cocultured with cerebellar astrocytes from newborn rats, a neural phenotype was achieved. This was determined by immunocytochemistry to GFAP, Nestin, or ß-Tubulin III and by morphological changes. It was achieved without the addition of exogenous differentiation factors. This demonstrates that placenta-derived MSCs may be able to differentiate into neural cell types when in direct contact with a neural environment.


Assuntos
Técnicas de Cultura de Células/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Neurônios/fisiologia , Placenta/citologia , Nicho de Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/fisiologia , Transdiferenciação Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Humanos , Neurogênese/fisiologia , Fenótipo , Gravidez , Ratos , Ratos Wistar
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