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1.
Carbohydr Polym ; 255: 117332, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436175

RESUMO

To fabricate a mucoadhesive hydrogel with superior properties for local delivery of cisplatin (CDDP) to colorectal cancer, a hardcore bottle-brush polymer (HCBBP) was developed through grafting of poly(acrylic acid) (PAA) on cellulose nanocrystals (CNC) at 6, 9 and 12 CNC:PAA w/w ratios. The developed materials were characterized by acid-base titrations, FT-IR, electron microscopy, muco-rheological behaviour in the presence of mucin, in vitro drug release and anticancer activity against human HCT-116 colorectal cancer cells. The results showed CNC-g-PAA9 to have superior rheological behavior in the presence of mucin compared to CNC and other gels under study indicating beneficial mucoadhesive characteristics. CNC-g-PAA9:CDDP complex showed slow CDDP release causing a significant increase in IC 50 of the drug (> 3-fold) against HCT116 cells. The developed CNC-PAA9 hydrogel showed no intrinsic cytotoxicity on its own. The results point to a great promise for CNC-g-PAA9 as mucoadhesive hydrogels for local platinum delivery in colorectal cancer.


Assuntos
Resinas Acrílicas/química , Antineoplásicos/farmacologia , Celulose/química , Cisplatino/farmacologia , Portadores de Fármacos , Hidrogéis/síntese química , Resinas Acrílicas/metabolismo , Antineoplásicos/metabolismo , Adesão Celular , Sobrevivência Celular/efeitos dos fármacos , Celulose/metabolismo , Cisplatino/metabolismo , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Células HCT116 , Humanos , Hidrogéis/metabolismo , Concentração Inibidora 50 , Cinética , Mucinas/metabolismo , Nanopartículas/química , Nanopartículas/ultraestrutura
2.
Int J Nanomedicine ; 15: 4793-4810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764921

RESUMO

Background: Platinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin's pharmacokinetics and safety profile. Purpose: This work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells' xenograft model in mice. Methods: Cell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells' xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses. Results: We observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq analysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug. Conclusion: Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Portadores de Fármacos/química , Espaço Intracelular/metabolismo , Nanomedicina/métodos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Life Sci ; 253: 117581, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32209424

RESUMO

AIMS: Cisplatin (CDDP) is an effective antineoplastic agent, however, its serious nephrotoxicity limits therapeutic use. Human growth hormone (hGH) has proved antioxidant and anti-inflammatory activities. The present study aimed to investigate the nephroprotective effects of hGH against CDDP-induced nephrotoxicity and the mechanisms underlying this nephroprotection. MAIN METHODS: Male albino rats injected with CDDP (7 mg/kg) and nephrotoxicity indices, oxidative stress and inflammatory biomarkers (high mobility group box protein-1 (HMGB-1), soluble epoxide hydrolase (sEH), and nuclear factor-kappa B (NF-κB)) were assessed. Also, insulin-like growth factor-1 (IGF-1) and Nuclear factor-erythroid-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway were assessed. KEY FINDINGS: hGH (1 mg/kg) improved kidney function and antioxidant systems and showed intact renal tubular epithelium. Cisplatin upregulated the HMGB-1/NF-κB and downregulated Nrf2/HO-1 pathways which were reversed by hGH and aligned with increased renal IGF-1 expression. Also, IGF-1/sEH crosstalk might be involved in hGH nephroprotection. Moreover, hGH downregulated HSP70 and caspase-3 expressions. SIGNIFICANCE: these results concluded that hGH can attenuate the inflammation and oxidative stress attained by CDDP probably through inhibition of Nrf2/HO-1 pathway. We also suggested that Keap1/Nrf2-mediated upregulation of the antioxidant HO-1 might inhibit HMGB-1/NF-κB signaling and thus provide the principal protection mechanism offered by hGH against CDDP-induced kidney injury.


Assuntos
Lesão Renal Aguda/prevenção & controle , Cisplatino/efeitos adversos , Hormônio do Crescimento/metabolismo , Heme Oxigenase-1/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Caspase 3/metabolismo , Cisplatino/metabolismo , Modelos Animais de Doenças , Epóxido Hidrolases/metabolismo , Hormônio do Crescimento/farmacologia , Proteínas HMGB/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Hormônio do Crescimento Humano , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais
4.
Am J Physiol Renal Physiol ; 318(4): F971-F978, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150447

RESUMO

Acute kidney injury (AKI) remains a major global healthcare problem, and there is a need to develop human-based models to study AKI in vitro. Toward this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces hepatitis A virus cellular receptor 1 (HAVCR1) and C-X-C motif chemokine ligand 8 (CXCL8) expression, DNA damage (γH2AX), and cell death in the organoids but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubule-specific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4 × 5 µM cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of cisplatin-induced injury, with the potential to identify new AKI biomarkers and develop better therapies.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Dano ao DNA , Túbulos Renais Proximais/efeitos dos fármacos , Organoides/efeitos dos fármacos , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Antineoplásicos/metabolismo , Células Cultivadas , Cisplatino/metabolismo , Relação Dose-Resposta a Droga , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Histonas/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Transportador 2 de Cátion Orgânico/metabolismo , Organoides/metabolismo , Organoides/patologia , Fatores de Tempo
5.
Sci Rep ; 10(1): 2717, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066812

RESUMO

Due to their high specific surface area, graphene oxide and graphene oxide-base nanoparticles have great potential both in dual-drug delivery and combination chemotherapy. Herein, we developed cisplatin (Pt) and doxorubicin (DOX) dual-drug-loaded PEGylated nano-graphene oxide (pGO) to facilitate combined chemotherapy in one system. In this study, nano-sized pGO-Pt/DOX ranged around 161.50 nm was fabricated and characterized using zeta-potential, AFM, TEM, Raman, UV-Vis, and FTIR analyses. The drug delivery efficacy of Pt was enhanced through the introduction of pGO, and the final weight ratio of DOX: Pt: pGO was optimized to 0.376: 0.376: 1. In vitro studies revealed that pGO-Pt/DOX nanoparticles could be effectively delivered into tumor cells, in which they induced prominent cell apoptosis and necrosis and exhibited higher growth inhibition than the single drug delivery system or free drugs. The pGO-Pt/DOX induced the most prominent cancer cell apoptosis and necrosis rate with 18.6%, which was observed almost 2 times higher than that of pGO-Pt or pGO-DOX groups. in the apoptosis and necrotic quadrants In vivo data confirmed that the pGO-Pt/DOX dual-drug delivery system attenuated the toxicity of Pt and DOX to normal organs compared to free drugs. The tumor inhibition data, histopathology observations, and immunohistochemical staining confirmed that the dual-drug delivery system presented a better anticancer effect than free drugs. These results clearly indicated that the pGO-Pt/DOX dual-drug delivery system provided the means for combination drug delivery in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Neoplasias Bucais/tratamento farmacológico , Nanopartículas/química , Animais , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cisplatino/metabolismo , Doxorrubicina/metabolismo , Portadores de Fármacos , Composição de Medicamentos/métodos , Feminino , Grafite/química , Humanos , Camundongos , Camundongos Nus , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Nanopartículas/administração & dosagem , Polietilenoglicóis/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Life Sci ; 244: 117299, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953157

RESUMO

AIMS: Notch signaling is highly implicated in several cancers and chemoresistance. Therefore, Notch-targeted therapies might be beneficial in enhancing chemotherapeutic effect and cancer regression. This study aimed to investigate implication of Notch in development and progression of solid Ehrlich carcinoma (SEC) and enhancement of anticancer effect of cisplatin (CIS) by addition of thymoquinone (TQ) and pentoxifylline (PTX) through modulation of Notch. MAIN METHODS: SEC was induced in mice as model for mammary carcinoma by s.c. injection of 1 × 106 Ehrlich cells into back of the mice. On 12th day, solid tumor was developed and mice were divided into seven groups; tumor control, early CIS (ECIS), ECIS + ETQ, ECIS + ETQ + EPTX, late CIS (LCIS), LCIS + LTQ, and LCIS + LTQ + LPTX. Early treatment was started on 12th day, whereas late treatment was begun on 19th day from tumor inoculation. At the endpoint, samples were collected for detection of Notch1, Hes1, Jagged1, ß-catenin, TNF-α, IL-6, IFN-γ, IL-2, VEGF, apoptosis, CD4, and CD8. KEY FINDINGS: Adding PTX and TQ to CIS significantly reduced Notch1, Hes1, Jagged1, ß-catenin, TNF-α, IL-6, IFN-γ, and VEGF with increment in IL-2, CD4, CD8, and apoptotic cells. Moreover, early treated groups showed remarkable attenuation in tumor growth and the relevant parameters compared to their counterpart later groups. SIGNIFICANCE: Addition of PTX with TQ to CIS showed a synergistic chemotherapeutic action and induced better oncostatic effect mainly through Notch suppression. Consequently, shutting Notch could be of great interest in promoting chemosensetivity and cancer control.


Assuntos
Benzoquinonas/farmacologia , Pentoxifilina/farmacologia , Receptores Notch/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Benzoquinonas/metabolismo , Carcinoma de Ehrlich/tratamento farmacológico , Carcinoma de Ehrlich/metabolismo , Cisplatino/metabolismo , Cisplatino/farmacologia , Feminino , Camundongos , Pentoxifilina/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Life Sci ; 244: 117280, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31926239

RESUMO

AIMS: Recently, chemoresistance has been recognized as an obstacle in the treatment of gastric cancer (GC). The aim of this study was to investigate the biological functions and underlying mechanisms of propofol in GC chemoresistance. MAIN METHODS: CCK-8 assay, flow cytometry and immunofluorescent staining were performed to assess the IC50 concentration, cell apoptosis and autophagy activity of cisplatin in both GC chemosensitive cells (SGC7901) and chemoresistant cells (SGC7901/CDDP). The expression pattern of MALAT1 in GC cells was detected by qRT-PCR. The shRNAs and overexpressing plasmids were employed for the loss or gain-of-function. Dual-luciferase reporter assay was subjected to verify the binding relationship between MALAT1 and miR-30e. Besides, ATG5 mRNA and protein levels were determined using qRT-PCR and western blot analysis. Furthermore, GC xenograft mice model was established to validate the in vitro findings. KEY FINDINGS: Chemoresistant GC cells presented higher IC50 of cisplatin, increased autophagy activity and stronger expression of MALAT1. The application of propofol promoted cell apoptosis and reduced the activity of autophagy through downregulating MALAT1. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 overexpression promoted autophagy in GC cells. Mechanistic researches demonstrated that MALAT1 could bind with miR-30e to regulate ATG5 expression, thus causing the suppression of autophagy. In vivo GC xenograft model treated with both propofol and cisplatin also showed significantly decreased tumor size and weight, which was enhanced by knockdown of MALAT1. SIGNIFICANCE: Altogether, our study revealed a novel mechanism of propofol of lncRNA MALAT1/miR-30e/ATG5 mediated autophagy-related chemoresistance in GC, casting new lights on the understanding of propofol.


Assuntos
MicroRNAs/genética , Propofol/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , China , Cisplatino/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Propofol/farmacologia , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Toxicol In Vitro ; 63: 104752, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31857146

RESUMO

Kidney is a major route of xenobiotic excretion, but the accuracy of preclinical data for predicting in vivo clearance is limited by species differences and non-physiologic 2D culture conditions. Microphysiological systems can potentially increase predictive accuracy due to their more realistic 3D environment and incorporation of dynamic flow. We used a renal proximal tubule microphysiological device to predict renal reabsorption of five compounds: creatinine (negative control), perfluorooctanoic acid (positive control), cisplatin, gentamicin, and cadmium. We perfused compound-containing media to determine renal uptake/reabsorption, adjusted for non-specific binding. A physiologically-based parallel tube model was used to model reabsorption kinetics and make predictions of overall in vivo renal clearance. For all compounds tested, the kidney tubule chip combined with physiologically-based modeling reproduces qualitatively and quantitatively in vivo tubular reabsorption and clearance. However, because the in vitro device lacks filtration and tubular secretion components, additional information on protein binding and the importance of secretory transport is needed in order to make accurate predictions. These and other limitations, such as the presence of non-physiological compounds such as antibiotics and bovine serum albumin in media and the need to better characterize degree of expression of important transporters, highlight some of the challenges with using microphysiological devices to predict in vivo pharmacokinetics.


Assuntos
Túbulos Renais Proximais/metabolismo , Modelos Biológicos , Reabsorção Renal , Técnicas de Cultura de Tecidos , Cádmio/metabolismo , Caprilatos/metabolismo , Cisplatino/metabolismo , Creatinina/metabolismo , Fluorcarbonetos/metabolismo , Gentamicinas/metabolismo , Humanos
9.
Br J Cancer ; 122(2): 221-232, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819184

RESUMO

BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses. METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects. RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment. CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Cisplatino/administração & dosagem , Glioma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Cisplatino/metabolismo , Feminino , Glioma/metabolismo , Glioma/patologia , Glioma/cirurgia , Glucose/metabolismo , Humanos , Ácido Láctico/metabolismo , Masculino , Microdiálise/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias
10.
Sci Rep ; 9(1): 17214, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748538

RESUMO

In this work the permeability of a model asymmetric plasma membrane, for ions, water and the anti-cancer drugs cisplatin and gemcitabine is studied by means of all-atom molecular dynamics simulations. It is shown for the first time that permeability of the highly curved membrane increases from one to three orders of magnitude upon membrane bending depending on the compound and the sign of curvature. Our results suggest that the membrane curvature could be an important factor of drug translocation through the membrane.


Assuntos
Permeabilidade da Membrana Celular , Membrana Celular/química , Membrana Celular/metabolismo , Cisplatino/metabolismo , Desoxicitidina/análogos & derivados , Bicamadas Lipídicas/metabolismo , Água/metabolismo , Animais , Antineoplásicos/metabolismo , Desoxicitidina/metabolismo , Humanos , Íons , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular
11.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500118

RESUMO

Cancer cells cope with high oxidative stress levels, characterized by a shift toward the oxidized form (GSSG) of glutathione (GSH) in the redox couple GSSG/2GSH. Under these conditions, the cytosolic copper chaperone Atox1, which delivers Cu(I) to the secretory pathway, gets oxidized, i.e., a disulfide bond is formed between the cysteine residues of the Cu(I)-binding CxxC motif. Switching to the covalently-linked form, sulfur atoms are not able to bind the Cu(I) ion and Atox1 cannot play an antioxidant role. Atox1 has also been implicated in the resistance to platinum chemotherapy. In the presence of excess GSH, the anticancer drug cisplatin binds to Cu(I)-Atox1 but not to the reduced apoprotein. With the aim to investigate the interaction of cisplatin with the disulfide form of the protein, we performed a structural characterization in solution and in the solid state of oxidized human Atox1 and explored its ability to bind cisplatin under conditions mimicking an oxidizing environment. Cisplatin targets a methionine residue of oxidized Atox1; however, in the presence of GSH as reducing agent, the drug binds irreversibly to the protein with ammine ligands trans to Cys12 and Cys15. The results are discussed with reference to the available literature data and a mechanism is proposed connecting platinum drug processing to redox and copper homeostasis.


Assuntos
Cisplatino/metabolismo , Proteínas de Transporte de Cobre/metabolismo , Glutationa/metabolismo , Chaperonas Moleculares/metabolismo , Oxirredução , Cisplatino/química , Cobre/metabolismo , Proteínas de Transporte de Cobre/química , Dissulfetos/química , Glutationa/química , Humanos , Metalochaperonas/metabolismo , Modelos Moleculares , Chaperonas Moleculares/química , Ligação Proteica , Conformação Proteica , Proteólise , Espécies Reativas de Oxigênio/metabolismo , Análise Espectral
12.
Nanoscale ; 11(41): 18946-18967, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31454005

RESUMO

The growth and breadth of nanoparticle (NP) research now encompasses many scientific and technologic fields, which has driven the want to control NP dimensions, structures and properties. Recent advances in NP synthesis, especially in solution phase synthesis, and characterization have made it possible to tune NP sizes and shapes to optimize NP properties for various applications. In this review, we summarize the general concepts of using solution phase chemistry to control NP nucleation and growth for the formation of monodisperse NPs with polyhedral, cubic, octahedral, rod, or wire shapes and complex multicomponent heterostructures. Using some representative examples, we demonstrate how to use these monodisperse NPs to tune and optimize NP catalysis of some important energy conversion reactions, such as the oxygen reduction reaction, electrochemical carbon dioxide reduction, and cascade dehydrogenation/hydrogenation for the formation of functional organic compounds under greener chemical reaction conditions. Monodisperse NPs with controlled surface chemistry, morphologies and magnetic properties also show great potential for use in biomedicine. We highlight how monodisperse iron oxide NPs are made biocompatible and target-specific for biomedical imaging, sensing and therapeutic applications. We intend to provide readers some concrete evidence that monodisperse NPs have been established to serve as successful model systems for understanding structure-property relationships at the nanoscale and further to show great potential for advanced nanotechnological applications.


Assuntos
Nanomedicina , Nanopartículas/química , Animais , Dióxido de Carbono/química , Catálise , Cisplatino/química , Cisplatino/metabolismo , Portadores de Fármacos/química , Técnicas Eletroquímicas , Química Verde , Neoplasias/diagnóstico por imagem
13.
Drug Deliv ; 26(1): 773-781, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31357890

RESUMO

Although convection-enhanced delivery (CED) can successfully facilitate a bypass of the blood brain barrier, its treatment efficacy remains highly limited in clinic. This can be partially attributed to the brain anisotropic characteristics that lead to the difficulties in controlling the drug spatial distribution. Here, the responses of six different drugs to the tissue anisotropy are examined through a parametric study performed using a multiphysics model, which considers interstitial fluid flow, tissue deformation and interlinked drug transport processes in CED. The delivery outcomes are evaluated in terms of the penetration depth and delivery volume for effective therapy. Simulation results demonstrate that the effective penetration depth in a given direction can be improved with the increase of the corresponding component of anisotropic characteristics. The anisotropic tissue permeability could only reshape the drug distribution in space but has limited contribution to the total effective delivery volume. On the other hand, drugs respond in different ways to the anisotropic diffusivity. The large delivery volumes of fluorouracil, carmustine, cisplatin and doxorubicin could be achieved in relatively isotropic tissue, while paclitaxel and methotrexate are able to cover enlarged regions into anisotropic tissues. Results obtained from this study serve as a guide for the design of CED treatments.


Assuntos
Barreira Hematoencefálica , Convecção , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/metabolismo , Anisotropia , Velocidade do Fluxo Sanguíneo , Barreira Hematoencefálica/metabolismo , Carmustina/administração & dosagem , Carmustina/metabolismo , Cisplatino/administração & dosagem , Cisplatino/metabolismo , Difusão , Doxorrubicina/administração & dosagem , Doxorrubicina/metabolismo , Líquido Extracelular/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/metabolismo , Metotrexato/administração & dosagem , Metotrexato/metabolismo , Modelos Teóricos , Paclitaxel/administração & dosagem , Paclitaxel/metabolismo , Permeabilidade , Pressão , Análise Espacial
14.
Food Chem Toxicol ; 132: 110652, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31255669

RESUMO

Cisplatin (CDDP) is a potent platinum-based chemotherapeutic agent used to treat solid tumors including colorectal cancer via inducing cytotoxicity. CDDP usage is limited due to the chemoresistance and associated adverse effects. A combinatorial regimen of phytochemicals with anticancer activity along with approved anticancer drugs seems to be a hopeful strategy against cancer treatment. Lotus-derived compounds such as neferine and isoliensinine have proven significant chemosensitizing activity in different cancer cells. Present study aims to compare chemosensitizing activity/anticancer potential of neferine/isoliensinine in combinatorial regimen with CDDP. Results documented that neferine/isoliensinine with CDDP augmented 'intracellular uptake of cisplatin' consequently apoptosis in HCT-15 cells exemplified by 'apoptotic morphological changes', 'S phase cell cycle arrest', 'ROS mediated oxidative stress' with the concomitant escalation in intracellular calcium & dissipation of MMP and activation of MAPK/PI3K/AKT pathway'. Furthermore, isoliensinine combination with CDDP exclusively enhanced CDDP uptake and induced more ROS-mediated apoptosis compared to other treatment regimens. Combination regimens induced downregulation of Bcl2 and upregulation of cytochrome c, caspase 3, 9, PARP cleavage indicating apoptosis induction through the intrinsic pathway. Thus, the results of the present study suggest that CDDP combination with neferine/isoliensinine augments the anticancer potential of CDDP in an additive manner and decrease CDDP dose requirement.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Cisplatino/farmacologia , Isoquinolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Cisplatino/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos
15.
Mol Biol Rep ; 46(5): 5033-5039, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31278563

RESUMO

Cisplatin is widely used as an anticancer drug in chemotherapy of human cancers. In the field of cancer therapy, nanoparticles modified with biocompatible copolymers are suitable vehicles to effectively deliver smaller doses of hydrophobic drugs such as cisplatin in the body. In this study, we investigated whether cisplatin-loaded iron oxide nanoparticles (IONPs) modified with chitosan can exert cytotoxic effects in the human breast cancer cell line MDA-MB-231. IONPs was synthesized using eucalyptus leaf extract as a reducing and stabilizing agent. MDA-MB-231 cells were treated with different concentrations of cisplatin, cisplatin-IONPs and cisplatin-IONPs-chitosan for 24 h. Apoptosis was confirmed by flow cytometry, whereas The mRNA and protein expression of pro- and anti-apoptotic molecules were measured using Real time RT-PCR and western blotting. Treatment with both cisplatin-IONPs and cisplatin-IONPs-chitosan showed a significantly higher cytotoxic effect in comparison to the free drug alone in MDA-MB-231 cells. The levels of apoptosis in cells treated with a combination of cisplatin-IONPs-chitosan were significantly higher compared with cisplatin-IONPs and cisplatin alone. The results of this study showed that the interaction between cisplatin and iron oxide nanoparticles modified with chitosan could enhance responsiveness to cisplatin in breast cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Nanopartículas Metálicas/uso terapêutico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Quitosana/uso terapêutico , Cisplatino/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Feminino , Compostos Férricos/uso terapêutico , Humanos , Nanopartículas/química
16.
Life Sci ; 231: 116557, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194994

RESUMO

AIMS: Vinegar-baked Radix Bupleuri (VBRB) potentiates the activity of anticancer drugs in the liver by increasing their hepatic distribution. However, this phenomenon may be associated with drug transporters. We investigated the effect of saikosaponin b2 (SSb2; the main component of VBRB) on the activity and expression of different drug transporters in both normal cells and those that overexpress the transporter. MAIN METHODS: The activities of transporters were analyzed by concentration of their cellular substrates. Concentrations of colchicine (substrate of Pgp and MRP1) and cisplatin (substrate of OCT2 and MRP2) were determined by high-performance liquid chromatography (HPLC). The concentration of rhodamine B was determined by flow cytometry. The expression of transporter gene and protein were determined by qRT-PCR and Western blotting analysis. KEY FINDINGS: SSb2 increased colchicine efflux in HEK293 cells by primarily increasing Mrp1 activity, independent of gene and protein expression. SSb2 enhanced Mrp2 function and increased cisplatin efflux in BRL3A cells by upregulating Mrp2 gene expression, with a marginal effect on Pgp in normal cells. SSb2 increased OCT2 activity in OCT2-HEK293 cells by increasing the expression of OCT2 protein and mRNA; however, SSb2 inhibited MRP2 activity in MRP2-HEK293 cells by decreasing MRP2 protein expression, and decreased Pgp and MRP1 activity in Pgp- and MRP1-HEK293 cells. SIGNIFICANCE: SSb2 might potentially be the key active component of VBRB that enhances the hepatotargeting of anticancer drugs through the inhibition of multidrug resistance-associated drug transporters (Pgp, MRP1, and MRP2) in an environment-dependent manner.


Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/metabolismo , Saponinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Cisplatino/análise , Cisplatino/metabolismo , Cisplatino/farmacologia , Colchicina/análise , Colchicina/metabolismo , Colchicina/farmacologia , Resistência a Múltiplos Medicamentos/fisiologia , Células HEK293 , Humanos , Medicina Tradicional Chinesa , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , RNA Mensageiro/metabolismo , Rodaminas/análise , Rodaminas/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
J Biol Chem ; 294(32): 11960-11968, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31217280

RESUMO

Cisplatin is the most commonly used chemotherapeutic drug for managing solid tumors. However, toxicity and the innate or acquired resistance of cancer cells to the drug limit its usefulness. Cisplatin kills cells by forming cisplatin-DNA adducts, most commonly the Pt-d(GpG) diadduct. We recently showed that, in mice, repair of this adduct 2 h following injection is controlled by two circadian programs. 1) The circadian clock controls transcription of 2000 genes in liver and, via transcription-directed repair, controls repair of the transcribed strand (TS) of these genes in a rhythmic fashion unique to each gene's phase of transcription. 2) The excision repair activity itself is controlled by the circadian clock with a single phase at which the repair of the nontranscribed strand (NTS) and the rest of the genome takes place. Here, we followed the repair kinetic for long periods genome-wide both globally and at single nucleotide resolution by the Excision Repair-sequencing (XR-seq) method to better understand cisplatin DNA damage and repair. We find that transcription-driven repair is nearly complete after 2 days, whereas weeks are required for repair of the NTS and the rest of the genome. TS repair oscillates in rhythmically expressed genes up to 2 days post injection, and in all expressed genes, we see a trend in TS repair with time from the 5' to 3' end. These findings help to understand the circadian- and transcription-dependent and -independent control of repair in response to cisplatin, and should aid in designing cisplatin chemotherapy regimens with improved therapeutic indexes.


Assuntos
Relógios Circadianos/fisiologia , Cisplatino/metabolismo , Adutos de DNA/metabolismo , Reparo do DNA , Fígado/metabolismo , Animais , Cisplatino/análise , Cisplatino/farmacologia , Adutos de DNA/análise , Dano ao DNA/efeitos dos fármacos , Feminino , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de DNA/métodos , Fatores de Tempo
18.
Life Sci ; 232: 116561, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247208

RESUMO

AIMS: The poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells. MAIN METHODS: Apoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis. KEY FINDINGS: Cisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process. SIGNIFICANCE: This study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.


Assuntos
Compostos de Bifenilo/farmacologia , Nitrofenóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Sirtuína 3/metabolismo , Sulfonamidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/metabolismo , Cisplatino/farmacologia , Feminino , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/fisiopatologia , Ovário/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Electrophoresis ; 40(18-19): 2329-2335, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31087392

RESUMO

Cisplatin and its second and third generation analogues are widely used in the treatment of cancer. To study their reactions with proteins, we present a method based on SDS-PAGE separation and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) for platinum detection in the reaction between human serum albumin (HSA) and cisplatin. We developed matrix-matched standards of HSA/cisplatin mixtures and used them to quantify the amount of adducts formed at different HSA:cisplatin ratios. We noted that cisplatin incubation with HSA resulted in the formation of higher order HSA n-mers, depending on the amount of cisplatin added. This caused a depletion of the HSA dimer bands, while the majority of HSA was present as the monomer. Inducing the formation of such higher molecular weight species may have an impact on the mode of action of metallodrugs.


Assuntos
Cisplatino/análise , Cisplatino/metabolismo , Espectrometria de Massas/métodos , Albumina Sérica Humana/metabolismo , Antineoplásicos/análise , Antineoplásicos/química , Antineoplásicos/metabolismo , Cisplatino/química , Humanos , Lasers , Albumina Sérica Humana/química
20.
Med Sci Monit ; 25: 2386-2396, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30938333

RESUMO

BACKGROUND Cisplatin-resistant gastric cancer (GC) occurs in patients with GC treated with cisplatin-based chemotherapy, which results in disease progression and early recurrence during the treatment. MATERIAL AND METHODS To understand the initiation and developmental mechanism underlying cisplatin-resistant GC, we developed cisplatin-resistant SGC7901 cells (SGC7901/DDP) from the parental cells (SGC7901/S) by continuous exposure to increasing concentrations of cisplatin and subjected these 2 cell lines to RNA sequencing analysis. The data were verified by quantitative polymerase chain reaction and their functional role was evaluated by cell counting kit 8 assay and cell apoptosis and cell cycle flow cytometric analysis. Bioinformatics analysis was performed to classify the differentially-expressed genes (DEGs) involved in the development of cisplatin resistance. RESULTS In comparison with SGC7901/S cells, SGC7901/DDP cells showed a total of 3165 DEGs (2014 upregulated and 1151 downregulated, fold change ≥2, and adjusted P value <0.001). qRT-PCR confirmed the reliability of the RNA sequencing results. Depletion of the top 5 upregulated mRNAs reversed the resistant index, increased apoptotic SGC7901/DDP cells, and arrested the cells at G2/M phase. Gene ontology analysis revealed that the DEGs mainly regulate metabolic process, immune system, locomotion, cell adhesion, cell growth, cell death, cytoskeleton organization, cell binding, signal transducing activity, and antioxidant activity. Kyoto Encyclopedia of Genes and Genomes analysis showed that the DEGs were mainly involved in the PI3K-Akt signaling pathway, Rap1 signaling pathway, proteoglycans in cancer, regulation of actin cytoskeleton, and pathways in cancer. CONCLUSIONS The present study is the first to interrogate mRNAs profiles in human GC cells with cisplatin resistance using RNA sequencing, which may assist in discovering potential therapeutic targets for cisplatin-resistant GC patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Gástricas/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/metabolismo , Cisplatino/farmacologia , Resistência a Múltiplos Medicamentos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , RNA Mensageiro/análise , Reprodutibilidade dos Testes , Transcriptoma/genética
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