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1.
Anticancer Res ; 40(1): 9-26, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892549

RESUMO

BACKGROUND/AIM: Inhibition of apoptosis is one of the hallmarks of cancer, and anti-apoptotic genes are often targets of genetic and epigenetic alterations. Cellular inhibitor of apoptosis 2 (cIAP2) has a role in degrading caspases by linking them to ubiquitin molecules, and is upregulated in triple-negative breast cancer (TNBC). Previous studies have demonstrated that cIAP2 may play a role in the epithelial-to-mesenchymal transition (EMT). MATERIALS AND METHODS: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, was administered to triple-negative breast cancer (TNBC) cells alone or in combination with epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor isolated from green tea. RESULTS: The compounds were able to decrease the expression of cIAP2 while increasing the expression of pro-apoptotic caspase 7. There were also changes in histone modifications, suggesting a role of epigenetic mechanisms in these changes in expression of cIAP2. These changes resulted in an increase in apoptosis. SAHA and EGCG were also capable of limiting TNBC cell migration across a fibronectin (FN) matrix. CONCLUSION: SAHA and EGCG reduce the metastatic potential of TNBC by inducing the apoptotic pathway.


Assuntos
Apoptose/efeitos dos fármacos , Proteína 3 com Repetições IAP de Baculovírus/genética , Catequina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Vorinostat/farmacologia , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Catequina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
2.
Chem Biol Interact ; 314: 108841, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586452

RESUMO

Despite the existence of multimodal therapy concepts, glioblastoma remains a tumor type with one of the worst prognoses. In particular, the poor prognosis is due to the lack of therapeutic efficacy of chemical agents and irradiation in hypoxic tumor areas. New therapeutic strategies could improve the treatment of glioblastoma. In this study, we investigated the therapeutic efficacy of a conjugate of cisplatin (DDP), a widely used chemotherapeutic agent, and betulinic acid (BA), a natural product from plane tree bark, in glioblastoma cells under different oxygen conditions. We investigated the effects of the BA-DDP conjugate κN',N''-{3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide} dichlorido platinum(II) (APC) and its precursor 3-acetyloxy-BA-28-[2-(2-aminoethyl)aminoethyl]amide (DE9B) on cytotoxicity, cell growth, apoptosis, migration and radiosensitivity compared to BA or DDP alone under different oxygen conditions. Based on the EC50 values, the precursor DE9B exhibited the strongest cytotoxic effects of the analyzed chemotherapeutic agents. The BA-DDP conjugate APC achieved a moderate cytotoxic effect in glioma cells. Both of the newly developed agents induced cell growth delay, apoptosis and inhibition of migration. Furthermore, additive effects could be achieved in combination with irradiation. In contrast to those of BA and DDP, the cell biological effects of APC and DE9B were not influenced by the oxygen concentration. In this study, the linking of BA and DDP did not produce a compound with additive therapeutic effects on glioblastoma cell lines in vitro. Nevertheless, the results of this study suggest that the precursor DE9B is an effective BA derivative for the treatment of glioblastoma in vitro.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/química , Complexos de Coordenação/farmacologia , Triterpenos/química , Antineoplásicos/química , Caspase 3/metabolismo , Caspase 7/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Glioma/metabolismo , Glioma/patologia , Humanos
3.
Int J Nanomedicine ; 14: 6325-6337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496689

RESUMO

Purpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined. Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer. Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 µM), 13 (10 µM) and cis-14 (10 µM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer. Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fulerenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Fulerenos/química , Células HL-60 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Estresse Oxidativo/efeitos dos fármacos , Quinidina/farmacologia , Carga Tumoral/efeitos dos fármacos , alfa-Tocoferol/farmacologia
4.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480250

RESUMO

Recently, we used a recombinant produced C-terminus (D194-F319) of the Clostridium perfringens enterotoxin (C-CPE) to functionalize gold nanoparticles (AuNPs) for a subsequent specific killing of claudin expressing tumor cells using the gold nanoparticle-mediated laser perforation (GNOME-LP) technique. For a future in vivo application, it will be crucial to know the physical parameters and the biological mechanisms inducing cell death for a rational adaptation of the system to real time situation. Regarding the AuNP functionalization, we observed that a relationship of 2.5 × 10-11 AuNP/mL to 20 µg/mL C-CPE maximized the killing efficiency. Regardingphysical parameters, a laser fluence up to 30 mJ/cm2 increased the killing efficiency. Independent from the applied laser fluence, the maximal killing efficiency was achieved at a scanning velocity of 5 mm/s. In 3D matrigel culture system, the GNOME-LP/C-CPE-AuNP completely destroyed spheroids composed of Caco-2 cells and reduced OE-33 cell spheroid formation. At the biology level, GNOME-LP/C-CPE-AuNP-treated cells bound annexin V and showed reduced mitochondria activity. However, an increased caspase-3/7 activity in the cells was not found. Similarly, DNA analysis revealed no apoptosis-related DNA ladder. The results suggest that the GNOME-LP/C-CPE-AuNP treatment induced necrotic than apoptotic reaction in tumor cells.


Assuntos
Apoptose , Enterotoxinas/química , Ouro/química , Lasers , Nanopartículas Metálicas/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Humanos
5.
Int J Nanomedicine ; 14: 4991-5015, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371943

RESUMO

Purpose: This study evaluates the cytotoxicity of AuNPs coated with polyallylamine (AuNPs-PAA) and conjugated or not to the epidermal growth factor receptor (EGFR)-targeting antibody Cetuximab (AuNPs-PAA-Ctxb) in normal human kidney (HK-2), liver (THLE-2) and microvascular endothelial (TIME) cells, and compares it with two cancer cell lines that are EGFR-overexpressing (A431) or EGFR-negative (MDA-MB-453). Results: Conjugation of Cetuximab to AuNPs-PAA increased the AuNPs-PAA-Ctxb interactions with cells, but reduced their cytotoxicity. TIME cells exhibited the strongest reduction in viability after exposure to AuNPs-PAA(±Ctxb), followed by THLE-2, MDA-MB-453, HK-2 and A431 cells. This cell type-dependent sensitivity was strongly correlated to the inhibition of thioredoxin reductase (TrxR) and glutathione reductase (GR), and to the depolarization of the mitochondrial membrane potential. Both are suggested to initiate apoptosis, which was indeed detected in a concentration- and time-dependent manner. The role of oxidative stress in AuNPs-PAA(±Ctxb)-induced cytotoxicity was demonstrated by co-incubation of the cells with N-acetyl L-cysteine (NAC), which significantly decreased apoptosis and mitochondrial membrane depolarization. Conclusion: This study helps to identify the cells and tissues that could be sensitive to AuNPs and deepens the understanding of the risks associated with the use of AuNPs in vivo.


Assuntos
Antioxidantes/metabolismo , Ouro/química , Nanopartículas Metálicas/química , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cetuximab/farmacologia , Endocitose/efeitos dos fármacos , Glutationa Redutase/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/ultraestrutura , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Tamanho da Partícula , Poliaminas/química , Substâncias Protetoras/farmacologia , Eletricidade Estática , Tiorredoxina Dissulfeto Redutase/metabolismo
6.
Chem Commun (Camb) ; 55(73): 10972-10975, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31453611

RESUMO

Platinum-resistant cancer cells are sensitive to changes in the levels of reactive oxidative species (ROS). Herein, we design a biotin-modified Ru(ii) complex as a photosensitizer (denoted as Ru-Biotin). Ru-Biotin can selectively target cancer cells and produce vast amounts of singlet oxygen under two-photon excitation at 820 nm leading to cell apoptosis. Ru-Biotin is therefore an excellent candidate to overcome platinum resistance via two-photon photodynamic therapy.


Assuntos
Antineoplásicos/farmacologia , Biotina/análogos & derivados , Biotina/farmacologia , Complexos de Coordenação/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Rutênio/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Biotina/síntese química , Biotina/efeitos da radiação , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/efeitos da radiação , Humanos , Raios Infravermelhos , Fotoquimioterapia/métodos , Fótons , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Oxigênio Singlete/metabolismo
7.
Nat Commun ; 10(1): 3887, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467299

RESUMO

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.


Assuntos
Antígenos/imunologia , Sistema Nervoso Central/imunologia , Doenças Desmielinizantes/imunologia , Células Precursoras de Oligodendrócitos/imunologia , Células Precursoras de Oligodendrócitos/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Astrócitos/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Caspase 3/metabolismo , Caspase 7/metabolismo , Diferenciação Celular , Sistema Nervoso Central/metabolismo , Citocinas/genética , Citocinas/metabolismo , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Expressão Gênica , Antígenos de Histocompatibilidade Classe I , Humanos , Interferon gama , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/metabolismo , Ovalbumina/metabolismo , Remielinização/imunologia , Linfócitos T
8.
Can J Physiol Pharmacol ; 97(9): 880-884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31365282

RESUMO

The objective of this study was to analyze the cardioprotective roles of 3 wild blueberry genotypes and one commercial blueberry genotype by measuring markers of oxidative stress and cell death in H9c2 cardiac cells exposed to doxorubicin. Ripe berries of the 3 wild blueberry genotypes were collected from a 10-year-old clearcut forest near Nipigon, Ontario, Canada (49°1'39″N, 87°52'21″W), whereas the commercial blueberries were purchased from a local grocery store. H9c2 cardiac cells were incubated with 15 µg gallic acid equivalent/mL blueberry extract for 4 h followed by 5 µM doxorubicin for 4 h, and oxidative stress and active caspase 3/7 were analyzed. The surface area as well as total phenolic content was significantly higher in all 3 wild blueberry genotypes compared with the commercial species. Increase in oxidative stress due to doxorubicin exposure was attenuated by pre-treatment with all 3 types of wild blueberries but not by commercial berries. Furthermore, increase in caspase 3/7 activity was also attenuated by all 3 wild genotypes as well. These data demonstrate that wild blueberry extracts can attenuate doxorubicin-induced damage to H9c2 cardiomyocytes through reduction in oxidative stress and apoptosis, whereas the commercial blueberry had little effect.


Assuntos
Mirtilos Azuis (Planta)/química , Citoproteção/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Extratos Vegetais/química , Ratos
9.
Anticancer Res ; 39(7): 3499-3506, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262874

RESUMO

BACKGROUND/AIM: The present study aimed to investigate the apoptotic effects of phenformin, a therapeutic agent for diabetes, on head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Cytotoxicity was measured by the MTT and live/dead cell assay. Phenformin-induced apoptotic FaDu cell death and its associated cellular signaling pathways were investigated by hematoxylin and eosin staining, 4',6-diamidino-2-phenylindole staining, caspase-3 activity assay, fluorescence-activated cell sorting analysis, and western blotting. RESULTS: Phenformin promoted death of and apoptotic processes in FaDu cells, including morphological alterations and nuclear condensation. Furthermore, treatment with phenformin increased caspase-3 activity and apoptotic populations via the caspase cascade through cleavage of capspase-8, -9, and -3 and poly(ADP-ribose) polymerase in FaDu cells. Moreover, phosphorylation levels of mitogen-activated protein kinases, nuclear factor-κB, and AKT were down-regulated in FaDu cells by phenformin. CONCLUSION: Phenformin induced death of FaDu cells via caspase-dependent extrinsic and intrinsic apoptosis pathways and is a promising novel therapeutic agent for HNSCC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fenformin/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Humanos
10.
Oxid Med Cell Longev ; 2019: 6325424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360296

RESUMO

The increased circulation of norepinephrine, found in the diseased heart as a result of sympathetic nervous system overactivation, is responsible for its cardiotoxic effects including pathological hypertrophy, cell death, and oxidative stress. Bucindolol is a third generation adrenergic blocker, which acts on the ß1 and ß2 receptors, and has additional α1 antagonist activity. Thus, the aim of this study was to investigate the action of bucindolol on oxidative stress, hypertrophy, cell survival, and cell death signaling pathways in H9c2 cardiac cells exposed to norepinephrine. H9c2 cells were incubated with 10 µM norepinephrine for 24 h in the presence or absence of bucindolol (10 µM) treatment for 8 h. Western blot was used to determine the expression of proteins for hypertrophy/survival and death signaling pathways. Flow cytometry was used to assess cell death via caspase-3/7 activity and propidium iodide and reactive oxygen species via measuring the fluorescence of CM-H2DCFDA. Norepinephrine exposure resulted in an increase in oxidative stress as well as cell death. This was accompanied by an increased protein expression of LC3B-II/I. The protein kinase B/mammalian target of the rapamycin (Akt/mTOR) pathway which is involved in cardiac remodeling process was activated in response to norepinephrine and was mitigated by bucindolol. In conclusion, bucindolol was able to modulate cardiac remodeling which is mediated by oxidative stress.


Assuntos
Norepinefrina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propanolaminas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Proteínas Associadas aos Microtúbulos/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
11.
Neurochem Res ; 44(8): 1878-1892, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31190314

RESUMO

Parkinson's disease (PD) is a prevalent, progressive, neurodegenerative disorder with no known cure. Oxidative stress has been found to play a significant role in its etiology, and the search for novel neuroprotective compounds that actively prevent disease progression is currently ongoing. Dithiolethiones are a group of sulfur-containing heterocyclic compounds found in cruciferous vegetables. Using the 6-hydroxydopamine (6-OHDA) model of PD, we tested a previously identified disubstituted dithiolethione 5-amino-3-thioxo-3H-(1,2) dithiole-4-carboxylic acid ethyl ester (ACDT) for its neuroprotective potential. Pretreatment of SH-SY5Y cells with ACDT led to a time- and concentration-dependent induction of the antioxidant glutathione (GSH). ACDT also diminished 6-OHDA-induced cell death, lactate dehydrogenase release, elevation of caspase 3/7 activity, and increase in levels of reactive oxygen species. Inhibition of the GSH-synthesizing enzyme glutamate-cysteine ligase catalytic subunit (GCLC) led a corresponding dissipation of ACDT's neuroprotective effects, hence underlining the importance of GSH in ACDT's neuroprotective response. ACDT caused the stabilization and nuclear translocation of nuclear factor erythroid-2 related factor (Nrf2), resulting in increased protein expression of the phase II enzyme NADPH:quinone oxidoreductase 1 (NQO1), and the excitatory amino acid cysteine membrane transporter (EAAT3). Interestingly, no changes in the levels of other Nrf2-dependent molecules including GCLC were observed, indicating the possible involvement of additional alternate mechanisms behind ACDT's GSH-inducing property. Collectively, the data demonstrated ACDT to be a promising new dithiolethione for the treatment of PD, with two modifiable functional groups offering additional avenues for enhanced pharmacological application.


Assuntos
Dissulfetos/farmacologia , Ésteres/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Compostos de Sulfidrila/farmacologia , Tionas/farmacologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Glutationa/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxidopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo
12.
Int J Biol Macromol ; 136: 266-274, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201909

RESUMO

Paclitaxel, an effective chemotherapeutic drug, is insoluble in aqueous solvents and is usually administered with excipients which have side effects. The use of this drug is also limited due to multi-drug resistance. In this study polysaccharide nanoparticles are used in the delivery of chemotherapeutic drug while minimizing side-effects, solubility issues and drug resistance. The use of biopolymers like galactoxyloglucan to synthesize nanoparticle makes it more biocompatible. This study involves the synthesis of PST-PTX nanoparticles using tamarind seed polysaccharide and Paclitaxel by epichlorohydrin crosslinking. The particles were further characterized by Dynamic Light Scattering (DLS), High-resolution transmission electron microscopy (HR-TEM) Fourier Transform Infrared Spectroscopy (FTIR) and UV-Visible spectroscopy. The cytotoxicity of PST-PTX nanoparticles in cancer cell lines and resistant cancer cell lines were determined by MTT assay. The quantitative analysis of cell death was determined by Annexin V dead cell assay, Caspase 3/7 assay and expression of pro-apoptotic protein Bax. The ability of the nanoparticle to overcome multi-drug resistance was evaluated by the expression of multidrug-resistant proteins P-glycoprotein (P-gp) and Breast cancer resistant protein (BCRP) in lung adenocarcinoma resistant cells (A549R). The present study provides evidence for the ability of PST-PTX nanoparticle to overcome multi-drug resistance and cause apoptotic cell death. The particle was found to be more effective than Paclitaxel in causing cell death in resistant cancer cells. Moreover, the particles were found to downregulate the expression of multi-drug resistant proteins P-gp and BCRP in resistant cell lines suggesting the ability of PST-PTX nanoparticles to overcome multi-drug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Galactose/química , Glucanos/química , Neoplasias Pulmonares/patologia , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacologia , 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/metabolismo , Apoptose/efeitos dos fármacos , Transporte Biológico , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Portadores de Fármacos/química , Humanos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Paclitaxel/metabolismo
13.
Genes (Basel) ; 10(7)2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31248009

RESUMO

Sponges, which are in close contact with numerous bacteria in prey/predator, symbiotic and pathogenic relationships, must provide an appropriate response in such situations. This starts with a discriminating recognition of the partner either by a physical contact or through secreted molecules or both. We investigated the expression of the Toll-like receptor, Caspase 3/7, Tumor Necrosis Factor receptor-associated factor 6, Bcl-2 homology protein-2 and macrophage expressed genes of axenic sponge cells in the presence of a symbiotic bacterium (Endozoicomonas sp. Hex311), a pathogen bacterium (Pseudoalteromonas sp. 1A1), their exoproducts and lipopolysaccharides. The vast majority of answers are in line with what could be observed with the symbiotic bacterium. The pathogenic bacterium seems to profit from the eukaryotic cell: suppression of the production of the antibacterial compound, inhibition of the apoptosis caspase-dependent pathway, deregulation of bacterial recognition. This work contributes new scientific knowledge in the field of immunology and apoptosis in early branching metazoan harboring within its tissue and cells a large number of symbiotic bacteria.


Assuntos
Gammaproteobacteria/fisiologia , Pseudoalteromonas/fisiologia , Suberites/imunologia , Suberites/microbiologia , Simbiose , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Gammaproteobacteria/efeitos dos fármacos , Gammaproteobacteria/metabolismo , Imunidade , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pseudoalteromonas/efeitos dos fármacos , Pseudoalteromonas/metabolismo , Pseudoalteromonas/patogenicidade , Suberites/genética , Receptores Toll-Like/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo
14.
Biomed Pharmacother ; 115: 108860, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31055235

RESUMO

EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve the progression-free survival of patients with non-small cell lung cancer (NSCLC). However, most patients inevitably developed drug resistance. EGFR T790 M mutation is the major mechanism for resistance to EGFR-TKIs and becomes an obstacle for the treatment of NSCLC patients with EGFR activating mutations. Besides, YAP/TAZ also confers resistance to EGFR-TKIs. Our previous study identified gossypol as a YAP/TAZ inhibitor. In the current study, we found that gossypol inhibited cell growth and induced apoptosis in H1975 cells harboring EGFRL858R/T790M. Also, gossypol treatment sensitized H1975 cells to EGFR-TKIs. Our mechanism studies showed that gossypol decreased the protein level of YAP/TAZ, which was abrogated by the proteasome inhibition. Moreover, over-expression of YAP/TAZ reversed the effects of gossypol on H1975 cells, and YAP/TAZ knockdown sensitized H1975 cells to gossypol treatment. Furthermore, gossypol reduced the protein level of EGFRL858R/T790M and inhibited the downstream ERK1/2 pathway in H1975 cells. Our findings suggested that gossypol might serve a promise drug candidate for overcoming EGFR-TKIs resistance by targeting both YAP/TAZ and EGFRL858R/T790M.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Anticoncepcionais Masculinos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Gossipol/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos Nus , Mutação
15.
J Enzyme Inhib Med Chem ; 34(1): 1110-1120, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31117890

RESUMO

New anticancer agents are highly needed to overcome cancer cell resistance. A novel series of pyrimidine pyrazoline-anthracene derivatives (PPADs) (4a-t) were designed and synthesised. The anti-liver cancer activity of all compounds was screened in vitro against two hepatocellular carcinoma (HCC) cell lines (HepG2 and Huh-7) as well as normal fibroblast cells by resazurin assay. The designed compounds 4a-t showed a broad-spectrum anticancer activity against the two cell lines and their activity was more prominent on cancer compared to normal cells. Compound 4e showed high potency against HepG2 and Huh-7 cell lines ((IC50=5.34 and 6.13 µg/mL, respectively) comparable to that of doxorubicin (DOX) activities. A structure activity relationship (SAR) has been investigated and compounds 4e, 4i, 4m, and 4q were the most promising anticancer agents against tested cell lines. These compounds induced apoptosis in HepG2 and Huh-7 cells through significant activation of caspase 3/7 at all tested concentrations. In conclusion, 4e could be a potent anticancer drug.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Drogas , Neoplasias Hepáticas/tratamento farmacológico , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
16.
Arch Virol ; 164(6): 1597-1607, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30949813

RESUMO

Hazara virus (HAZV) is closely related to Crimean-Congo hemorrhagic fever virus (CCHFV), but differs in that it is non-pathogenic to humans. Since HAZV was isolated for the first time in 1954, the biological characteristics of this virus, particularly its behavior within culture cells, have not been well-studied, despite its importance as a surrogate model for CCHFV. Nucleoprotein (N) is the main component of viral nucleocapsid and is the most abundant virion protein, it is believed to play a pivotal role in the viral lifecycle. Generation of a series of anti-HAZV N monoclonal antibodies has enabled us to directly examine the involvement of this protein on viral growth. Observation of HAZV-infected cells revealed that this infection caused apoptosis, which was further characterized by DNA ladder and elevated caspase-3/7 activity. HAZV titers initially increased in cell culture, but after reaching the peak titer began to rapidly decline. HAZV particles were found to be very unstable in culture medium at 37 °C, and virus particles tend to lose infectivity at that point. HAZV N appears to inhibit apoptosis, thus can potentially support efficient viral propagation.


Assuntos
Anticorpos Monoclonais/farmacologia , Infecções por Bunyaviridae/virologia , Nairovirus/crescimento & desenvolvimento , Nucleoproteínas/antagonistas & inibidores , Carga Viral/efeitos dos fármacos , Células A549 , Animais , Anticorpos Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Infecções por Bunyaviridae/metabolismo , Células COS , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Cães , Humanos , Células Madin Darby de Rim Canino , Nairovirus/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores
17.
Molecules ; 24(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003438

RESUMO

The results of our previous research indicated that some derivatives of benzofurans, particularly halogeno-derivatives, are selectively toxic towards human leukemia cells. Continuing our work with this group of compounds we here report new data on the synthesis as well as regarding the physico-chemical and biological characterization of fourteen new derivatives of benzofurans, including six brominated compounds. The structures of all new compounds were established by spectroscopic methods (1H- and, 13C-NMR, ESI MS), and elemental analyses. Their cytotoxicity was evaluated against K562 (leukemia), MOLT-4 (leukemia), HeLa (cervix carcinoma), and normal cells (HUVEC). Five compounds (1c, 1e, 2d, 3a, 3d) showed significant cytotoxic activity against all tested cell lines and selectivity for cancer cell lines. The SAR analysis (structure-activity relationship analysis) indicated that the presence of bromine introduced to a methyl or acetyl group that was attached to the benzofuran system increased their cytotoxicity both in normal and cancer cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Antineoplásicos/química , Benzofuranos/química , Caspase 3/metabolismo , Caspase 7/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50
18.
Food Chem Toxicol ; 129: 87-96, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31029719

RESUMO

Amitraz is a neurotoxic formamidine pesticide that induces cell death in hippocampal neurons, although its mechanisms are unknown. Amitraz produces reactive oxygen species (ROS), which could lead to cell death. Amitraz was shown to induce different cytochrome P450 (CYP) isoenzymes involved with ROS and apoptotic cell death induction. Finally, amitraz was described to decrease the activity of antioxidant enzymes regulated through KEAP1/NRF2 pathway, thus likely leading to a reduction of ROS elimination and to cell death induction. We evaluated the effect of amitraz or BTS-27271 co-treatment with or without the antioxidant N-acetylcysteine and/or the unspecific CYP inhibitor 1-aminobenzotriazole on cell viability and its related mechanisms in wild type and silenced primary hippocampal neurons after 24 h treatment. We observed that amitraz produced oxidative stress and CYPs induction leading to apoptotic cell death. ROS generation was partially mediated by CYPs induction and downregulation of NRF2-pathway through KEAP1 overexpression. These data could help explain the mechanism by which amitraz induces cell death and oxidative stress and provide a therapeutic strategy to protect against this effect in case of poisoning.


Assuntos
Amidinas/toxicidade , Morte Celular/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Hipocampo/efeitos dos fármacos , Inseticidas/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Toluidinas/toxicidade , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Células Cultivadas , Sistema Enzimático do Citocromo P-450/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hipocampo/citologia , Fator 2 Relacionado a NF-E2/genética , Neurônios/efeitos dos fármacos , Gravidez , Ratos Wistar
19.
Eur J Pharmacol ; 854: 194-200, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30981767

RESUMO

In the present study, a series of L-valine derived boroxazolidones, previously synthesized and reported to have residual activity in a human epithelial cell line, have been evaluated in vitro for their anti-glioblastoma activity. A boroxazolidone derivative containing 2,4-difluorophenyl moieties (6) was found to have higher cytotoxicity than the standard drug, Temozolomide (TMZ). Compound 6 was found to exhibit dose-dependent growth inhibitory effects with an IC50 of 49 µM and 53 µM for LN229 and SNB19 cells, respectively. Additionally, 6 was assessed for its role in apoptosis, caspase 3/7 activation and oxidative stress in SNB19 and LN229 cells. SNB19 cells treated with 6 showed 45.3% apoptosis in the population, while TMZ had 24.7%. In LN229 cells, the percentage of apoptotic cells treated with compound 6 and TMZ were the same. Both 6 and TMZ induced apoptosis through the activation of caspase 3/7 in SNB19 and LN229 cells. Interestingly, 6 exhibited a higher effectivity in promoting reactive oxygen species production in LN229, while it was 6-fold less in SNB19. Boroxazolidone-treated GBM cell lines increased reactive oxygen species production, suggesting that such species may be interlinked with the observed programmed cell death. Additionally, the treatment of both GBM cell lines with 6 led to G2/M phase arrest. The magnitude of anti-GBM effect of 6 is significantly higher than the known chemotherapeutic agent TMZ. This work further demonstrates the anticancer properties of L-valine derived boroxazolidones, adding another potential derivative to the collection of promising chemotherapeutic agents for GBM treatment.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Glioblastoma/patologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Valina/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
20.
Biochimie ; 162: 229-238, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30954547

RESUMO

Lipopolysaccharide (LPS) as a component of the outer structure of cell wall of gram-negative bacteria, could induce apoptosis in the intestinal endocrine cell line STC-1. However, the signaling cascades involved in this process have not been elucidated. Hence, we investigated the mechanism of cell apoptosis and hyposecretion of glucagon-like peptide 1 (GLP-1) induced by LPS in the GLUTag enteroendocrine cell line. LPS decreased the cell viability of GLUTag cells, up-regulated the TNF-α level, induced the apoptosis and down-regulated the mRNA and protein levels of GLP-1. In addition, TNF-α promoted LPS-induced apoptosis of GLUTag cells through mediating the formation of the RIP1/RIP3 necrosome. RIP1 and RIP3 knockdown increased cell viability, the mRNA and protein levels of GLP-1 and the mTOR signaling pathway-related proteins (p-mTOR and p-S6), and decreased the relative caspase 3/7 activity, cell apoptosis and ROS production. Further studies showed that ROS inhibited the mTOR signaling pathway. Moreover, the antioxidant N-acetyl-l-cysteine increased cell viability, GLP-1 expressions and the mTOR signaling pathway-related proteins, and inhibited the ROS production. However, the mTOR specific inhibitor (Rapa) reversed all these above effects. Taken together, our result revealed that LPS induced the apoptosis of GLUTag cells and GLP-1 hyposecretion through the RIP/ROS/mTOR pathway.


Assuntos
Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Lipopolissacarídeos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Acetilcisteína/química , Animais , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular , Proteínas Ativadoras de GTPase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Serina-Treonina Quinases TOR/metabolismo
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