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1.
Yonsei Med J ; 61(9): 750-761, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882759

RESUMO

PURPOSE: Gastric cancer (GC) is a malignant tumor with a high mortality rate. Drug resistance is a major obstacle to GC therapy. This study aimed to investigate the role and mechanism of exosomal circPRRX1 in doxorubicin resistance in GC. MATERIALS AND METHODS: HGC-27 and AGS cells were exposed to different doses of doxorubicin to construct doxorubicin-resistant cell lines. Levels of circPRRX1, miR-3064-5p, and nonreceptor tyrosine phosphatase 14 (PTPN14) were detected by quantitative real-time PCR or Western blot assay. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, transwell, and Western blot assays were used to explore the function of circPRRX1 in GC cells. Interactions among circPRRX1, miR-3064-5p, and PTPN14 were confirmed by dual-luciferase reporter assay. The in vivo function of circPRRX1 was analyzed in a xenograft tumor model. RESULTS: CircPRRX1 was highly expressed in doxorubicin-resistant GC cell lines. Knockdown of circPRRX1 reversed doxorubicin resistance in doxorubicin-resistant GC cells. Additionally, extracellular circPRRX1 was carried by exosomes to spread doxorubicin resistance. CircPRRX1 silencing reduced doxorubicin resistance by targeting miR-3064-5p or regulating PTPN14. In GC patients, high levels of circPRRX1 in serum exosomes were associated with poor responses to doxorubicin treatment. Moreover, depletion of circPRRX1 reduced doxorubicin resistance in vivo. CONCLUSION: CircPRRX1 strengthened doxorubicin resistance by modulating miR-3064-5p/PTPN14 signaling and might be a therapeutic target for GC patients.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio , Humanos , MicroRNAs/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
2.
Int J Nanomedicine ; 15: 6167-6182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922000

RESUMO

Background: Among the novel cancer treatment strategies, combination therapy is a cornerstone of cancer therapy. Materials and Methods: Here, combination therapy with targeted polymer, magnetic hyperthermia and chemotherapy was presented as an effective therapeutic technique. The DOX-loaded PLA-PEG-FA magnetic nanoparticles (nanocarrier) were prepared via a double emulsion method. The nanocarriers were characterized by particle size, zeta potential, morphology, saturation magnetizations and heat generation capacity, and the encapsulation efficiency, drug content and in-vitro drug release for various weight ratios of PLA:DOX. Then, cytotoxicity, cellular uptake and apoptosis level of nanocarrier-treated cells for HeLa and CT26 cells were investigated by MTT assay, flow cytometry, and apoptosis detection kit. Results and Conclusions: The synthesized nanoparticles were spherical in shape, had low aggregation and considerable magnetic properties. Meanwhile, the drug content and encapsulation efficiency of nanoparticles can be achieved by varying the weight ratios of PLA:DOX. The saturation magnetizations of nanocarriers in the maximum applied magnetic field were 59/447 emu/g and 28/224 emu/g, respectively. Heat generation capacity of MNPs and nanocarriers were evaluated in the external AC magnetic field by a hyperthermia device. The highest temperature, 44.2°C, was measured in the nanocarriers suspension at w/w ratio 10:1 (polymer:DOX weight ratio) after exposed to the magnetic field for 60 minutes. The encapsulation efficiency improved with increasing polymer concentration, since the highest DOX encapsulation efficiency was related to the nanocarriers' suspension at w/w ratio 50:1 (79.6 ± 6.4%). However, the highest DOX loading efficiency was measured in the nanocarriers' suspension at w/w ratio 10:1 (5.14 ± 0.6%). The uptake efficiency and apoptosis level of nanocarrier-treated cells were higher than those of nanocarriers (folic acid free) and free DOX-treated cells in both cell lines. Therefore, this targeted nanocarrier may offer a promising nanosystem for cancer-combined chemotherapy and hyperthermia.


Assuntos
Doxorrubicina/farmacologia , Ácido Fólico/farmacologia , Hipertermia Induzida , Nanopartículas de Magnetita/química , Neoplasias/terapia , Polietilenoglicóis/química , Animais , Apoptose/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Células HeLa , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Tamanho da Partícula , Polietilenoglicóis/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática
3.
Int J Nanomedicine ; 15: 6385-6399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922007

RESUMO

Purpose: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions. Methods: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected. Results: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter's lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines. Conclusion: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.


Assuntos
Portadores de Fármacos/química , Esomeprazol/farmacologia , Sistema Fagocitário Mononuclear/citologia , Nanopartículas/química , Células A549 , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transporte Biológico , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Endocitose , Esomeprazol/farmacocinética , Esomeprazol/uso terapêutico , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Células RAW 264.7 , Distribuição Tecidual/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo
4.
Anticancer Res ; 40(10): 5371-5378, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988856

RESUMO

BACKGROUND/AIM: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability. MATERIALS AND METHODS: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay. RESULTS: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h. CONCLUSION: Dox-TSPO is a promising candidate for targeted and directed cancer treatment of CRC liver metastases.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/farmacologia , Pró-Fármacos/farmacologia , Receptores de GABA/genética , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Linhagem Celular Tumoral , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Humanos , Pró-Fármacos/química , Receptores de GABA/química
5.
Int J Nanomedicine ; 15: 5165-5177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764943

RESUMO

Background: The integration of NIR photothermal therapy and chemotherapy is considered as a promising technique for future cancer therapy. Hollow Prussian nanospheres have attracted much attention due to excellent near-infrared photothermal conversion effect and drug-loading capability within an empty cavity. However, to date, the hollow Prussian nanospheres have been prepared by a complex procedure or in organic media, and their shell thickness and size cannot be controlled. Thus, a simple and controllable route is highly desirable to synthesize hollow Prussian nanospheres with controllable parameters. Materials and Methods: Here, in our designed synthesis route, the traditional FeCl3 precursor was replaced with Fe2O3 nanospheres, and then the Prussian blue (PB) nanoparticles were engineered into hollow-structured PB (HPB) nanospheres through an interface reaction, where the Fe2O3 colloidal template provides Fe3+ ions. The reaction mechanism and control factors of HPB nanospheres were systematically investigated. Both in vitro and in vivo biological effects of the as-synthesized HPB nanospheres were evaluated in detail. Results: Through systematical experiments, a solvent-mediated interface reaction mechanism was put forward, and the parameters of HPB nanospheres could be easily adjusted by growth time and template size under optimal water and ethanol ratio. The in vitro tests show the rapid and remarkable photothermal effects of the as-prepared HPB nanospheres under NIR laser irradiation (808 nm). Meanwhile, HPB nanospheres also demonstrated a high DOX loading capacity of 440 mg g-1 as a drug carrier, and the release of the drug can be regulated by the heat from PB shell under the exposure of an NIR laser. The in vivo experiments confirmed the outstanding performance of HPB nanospheres in photothermal/chemo-synergistic therapy of cancer. Conclusion: A solvent-mediated template route was developed to synthesize hollow Prussian blue (HPB) nanospheres in a simple and controllable way. The in vitro and in vivo results demonstrate the as-synthesized HPB nanospheres as a promising candidate due to their low toxicity and high efficiency for cancer therapy.


Assuntos
Portadores de Fármacos/química , Ferrocianetos/química , Nanosferas/química , Fototerapia/métodos , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Compostos Férricos/química , Humanos , Hipertermia Induzida
6.
Int J Nanomedicine ; 15: 4825-4845, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753868

RESUMO

Background: Nanosized drug delivery systems (NDDSs) have shown excellent prospects in tumor therapy. However, insufficient penetration of NDDSs has significantly impeded their development due to physiological instability and low passive penetration efficiency. Methods: Herein, we prepared a core cross-linked pullulan-modified nanosized system, fabricated by visible-light-induced diselenide bond cross-linked method for transporting ß-Lapachone and doxorubicin prodrug (boronate-DOX, BDOX), to improve the physiological stability of the NDDSs for efficient passive accumulation in tumor blood vessels (ß-Lapachone/BDOX-CCS). Additionally, ultrasound (US) was utilized to transfer ß-Lapachone/BDOX-CCS around the tumor vessel in a relay style to penetrate the tumor interstitium. Subsequently, ß-Lapachone enhanced ROS levels by overexpressing NQO1, resulting in the transformation of BDOX into DOX. DOX, together with abundant levels of ROS, achieved synergistic tumor therapy. Results: In vivo experiments demonstrated that ultrasound (US) + cross-linked nanosized drug delivery systems (ß-Lapachone/BDOX-CCS) group showed ten times higher DOX accumulation in the tumor interstitium than the non-cross-linked (ß-Lapachone/BDOX-NCS) group. Conclusion: Thus, this strategy could be a promising method to achieve deep penetration of NDDSs into the tumor.


Assuntos
Doxorrubicina/uso terapêutico , Nanopartículas/química , Naftoquinonas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Ultrassonografia , Animais , Ácidos Borônicos/química , Permeabilidade Capilar/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Feminino , Glucanos/química , Células Hep G2 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftoquinonas/farmacocinética , Tamanho da Partícula , Pró-Fármacos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual/efeitos dos fármacos
7.
Int J Nanomedicine ; 15: 4483-4500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606690

RESUMO

Purpose: Tumor metastasis and drug resistance have always been vital aspects to cancer mortality and prognosis. To compromise metastasis and drug resistance, a nanoparticle IPPD-PHF2 (IR780/PLGA-PEI(Dox)-PHF2) has been engineered to accomplish efficient targeted epigenotherapy forced by PHF2-induced MET (mesenchymal to epithelial transition). Materials and Methods: IPPD-PHF2 nanoparticle was synthesized and characterized by several analytical techniques. The transfection efficiency of IPP-PHF2 (IR780/PLGA-PEI-PHF2) was compared with PP-PHF2 (PLGA-PEI-PHF2) in vitro by WB and in vivo by IHC, and the cytotoxicity of IPP was compared with Lipo2000 in vitro by CCK8 assay. The inhibition of cancer cell migration caused by PHF2-upregulation was tested by wound healing assay, and the enhanced chemotherapeutic sensitivity was detected by flow cytometry. Tumor-targeting property of IPPD-PHF2 was proved by fluorescent imaging in vivo with MDA-MB-231 tumor-bearing nude mice. Except for fluorescent imaging ability, considerable photoacoustic signals of IPPD-PHF2 at tumor sites were verified. The anti-tumor activity of IPPD-PHF2 was investigated using in vivo human breast cancer MDA-MB-231 cell models. Results: Tumor-targeting nanoparticle IPPD-PHF2 had an average size of about 319.2 nm, a stable zeta potential at about 38 mV. The encapsulation efficiency of doxorubicin was around 39.28%, and the adsorption capacity of plasmids was about 64.804 µg/mg. Significant up-regulation of PHF2 induced MET and caused reduced migration as well as enhanced chemotherapeutic sensitivity. Either IPPD (IR780/PLGA-PEI(Dox)) or IPP-PHF2 (IR780/PLGA-PEI-PHF2) presented minor therapeutic effects, whereas IPPD-PHF2 specifically accumulated within tumors, showed extraordinary transfection efficiency specifically in tumor sites, acted as inhibitors of metastasis and proliferation, and presented good multimodality imaging potentials in vivo. Conclusion: IPPD-PHF2 NPs is a promising tool to bring epigenotherapy into a more practical era, and the potential application of harm-free multimodality imaging guidance is of great value.


Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transfecção , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Indóis/química , Camundongos Nus , Nanopartículas/ultraestrutura , Metástase Neoplásica , Técnicas Fotoacústicas , Polietilenoimina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
8.
Gene ; 759: 145000, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32717310

RESUMO

Upregulation of the ATP-binding cassette (ABC) transporter is one of the most important factors leading to multidrug resistance (MDR) in several types of cancer. In the present study, we investigated the ability of rucaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor which is currently in clinical development, on overcoming ABC transporters-mediated MDR in cervical cancer cell lines. Rucaparib significantly enhanced the cytotoxic effects of a series of conventional chemotherapeutic drugs in drug resistance cervical cancer cell lines. Moreover, rucaparib significantly increased the accumulation of rhodamine 123 in doxorubicin- and paclitaxel-resistance cervical cancer cell lines. In addition, rucaparib significantly increased the accumulation of tritium-labeled chemotherapeutic drugs in drug resistance cervical cancer cells, and decrease the efflux of tritium-labeled chemotherapeutic drugs. Molecular docking study indicated that rucaparib could bind to the active site of the ABC transporters. The present study indicated that rucaparib could antagonize MDR in cervical cancer cells by blocking the function of ABC transporters. The results obtained in the present study provide the potential possibilities that the combination of rucaparib with other chemotherapeutic agents may benefit patients with cervical cancer.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Indóis/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias do Colo do Útero/metabolismo , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Ligação Proteica
9.
J Vis Exp ; (160)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32658190

RESUMO

Due to drug resistance and toxicity in healthy cells, use of doxorubicin (DOX) has been limited in clinical cancer therapy. This protocol describes the designing of poly(ethylenimine) grafted with polyethylene glycol (PEI-g-PEG) copolymer functionalized gold nanoparticles (AuNPs) with loaded aptamer (AS1411) and DOX through amide reactions. AS1411 is specifically bonded with targeted nucleolin receptors on cancer cells so that DOX targets cancer cells instead of healthy cells. First, PEG is carboxylated, then grafted to branched PEI to obtain a PEI-g-PEG copolymer, which is confirmed by 1H NMR analysis. Next, PEI-g-PEG copolymer coated gold nanoparticles (PEI-g-PEG@AuNPs) are synthesized, and DOX and AS1411 are covalently bonded to AuNPs gradually via amide reactions. The diameter of the prepared AS1411-g-DOX-g-PEI-g-PEG@AuNPs is ~39.9 nm, with a zeta potential of -29.3 mV, indicating that the nanoparticles are stable in water and cell medium. Cell cytotoxicity assays show that the newly designed DOX loaded AuNPs are able to kill cancer cells (A549). This synthesis demonstrates the delicate arrangement of PEI-g-PEG copolymers, aptamers, and DOX on AuNPs that are achieved by sequential amide reactions. Such aptamer-PEI-g-PEG functionalized AuNPs provide a promising platform for targeted drug delivery in cancer therapy.


Assuntos
Aptâmeros de Nucleotídeos/química , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Ouro/química , Nanopartículas Metálicas/química , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Células A549 , Técnicas de Química Sintética , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Humanos , Oligodesoxirribonucleotídeos/química , Polietilenoimina/química
10.
PLoS One ; 15(6): e0235090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569270

RESUMO

Tumor is a prevalent great threat to public health worldwide and multidrug resistance (MDR) of tumor is a leading cause of chemotherapy failure. Nanomedicine has shown prospects in overcoming the problem. Doxorubicin (DOX), a broad-spectrum anticancer drug, showed limited efficacy due to MDR. Herein, a doxorubicin containing pectin nanocell (DOX-PEC-NC) of core-shell structure, a pectin nanoparticle encapsulated with liposome-like membrane was developed. The DOX-PEC-NC, spheroid in shape and sized around 150 nm, exerted better sustained release behavior than doxorubicin loading pectin nanoparticle (DOX-PEC-NP) or liposome (DOX-LIP). In vitro anticancer study showed marked accumulation of doxorubicin in different tumor cells as well as reversal of MDR in HepG2/ADR cells and MCF-7/ADR cells caused by treatment of DOX-PEC-NC. In H22 tumor-bearing mice, DOX-PEC-NC showed higher anticancer efficacy and lower toxicity than doxorubicin. DOX-PEC-NC can improve anticancer activity and reduce side effect of doxorubicin due to increased intracellular accumulation and reversal of MDR in tumor cells, which may be a promising nanoscale drug delivery vehicle for chemotherapeutic agents.


Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/química , Pectinas/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Nanopartículas/ultraestrutura , Baço/patologia , Timo/patologia
11.
Proc Natl Acad Sci U S A ; 117(27): 15862-15873, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32561647

RESUMO

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.


Assuntos
Albuminúria/metabolismo , Nefropatias/metabolismo , Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Transdução de Sinais/fisiologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Benzazepinas/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas , Modelos Animais de Doenças , Regulação para Baixo , Doxorrubicina/farmacologia , Humanos , Insulina/metabolismo , Nefropatias/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neuropeptídeo Y/farmacologia , Neuropeptídeo Y/urina , Podócitos/metabolismo , Proteômica , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Int J Nanomedicine ; 15: 3319-3331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494132

RESUMO

Background: It is of great significance to develop intelligent co-delivery systems for cancer chemotherapy with improved therapeutic efficacy and few side-effects. Materials and Methods: Here, we reported a co-delivery system based on pH-sensitive polyprodrug micelles for simultaneous delivery of doxorubicin (DOX) and paclitaxel (PTX) as a combination chemotherapy with pH-triggered drug release profiles. The physicochemical properties, drug release profiles and mechanism, and cytotoxicity of PTX/DOX-PMs have been thoroughly investigated. Results and Discussion: The pH-sensitive polyprodrug was used as nanocarrier, and PTX was encapsulated into the micelles with high drug-loading content (25.6%). The critical micelle concentration (CMC) was about 3.16 mg/L, indicating the system could form the micelles at low concentration. The particle size of PTX/DOX-PMs was 110.5 nm, and increased to approximately 140 nm after incubation for 5 days which showed that the PTX/DOX-PMs had high serum stability. With decrease in pH value, the particle size first increased, and thenwas no longer detectable. Similar change trend was observed for CMC values. The zetapotential increased sharply with decrease in pH. These results demonstrated the pHsensitivity of PTX/DOX-PMs. In vitro drug release experiments and study on release mechanism showed that the drug release rate and accumulative release for PTX and DOX were dependent on the pH, showing the pH-triggered drug release profiles. Cytotoxicity assay displayed that the block copolymer showed negligible cytotoxicity, while the PTX/DOX-PMs possessed high cytotoxic effect against several tumor cell lines compared with free drugs and control. Conclusion: All the results demonstrated that the co-delivery system based on pH-sensitive polyprodrug could be a potent nanomedicine for combination cancer chemotherapy. In addition, construction based on polyprodrug and chemical drug could be a useful method to prepare multifunctional nanomedicine.


Assuntos
Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Micelas , Neoplasias/tratamento farmacológico , Paclitaxel/uso terapêutico , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Células NIH 3T3 , Neoplasias/patologia , Paclitaxel/farmacologia , Tamanho da Partícula , Polímeros/química , Eletricidade Estática
13.
Clin Sci (Lond) ; 134(12): 1305-1318, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32478397

RESUMO

Podocyte injury and loss contribute to proteinuria, glomerulosclerosis and eventually kidney failure. Recent studies have demonstrated that the loss of Kruppel-like factor 15 (KLF15) in podocytes increases the susceptibility to injury; however, the mechanism underlying the protective effects on podocyte injury remains incompletely understood. Herein, we showed that KLF15 ameliorates podocyte injury through suppressing NFAT signaling and the salutary effects of the synthetic glucocorticoid dexamethasone in podocyte were partially mediated by the KLF15-NFATc1 axis. We found that KLF15 was significantly reduced in glomerular cells of proteinuric patients and in ADR-, LPS- or HG-treated podocyets in vitro. Overexpression of KLF15 attenuated podocyte apoptosis induced by ADR, LPS or HG and resulted in decreased expression of pro-apoptotic Bax and increased expression of anti-apoptotic Bcl-2. Conversely, the flow cytometry analysis and TUNEl assay demonstrated that loss of KLF15 accelerated podocyte apoptosis and we further found that 11R-VIVIT, a specific NFAT inhibitor, and NFATc1-siRNA rescued KLF15-deficient induced podocyte apoptosis. Meanwhile, Western blot and RT-qPCR showed that the expression of NFATc1 was up-regulated in KLF15 silenced podocytes and reduced in KLF15 overexpressed podocytes. Mechanistically, ChIP analysis showed that KLF15 bound to the NFATc1 promoter region -1984 to -1861base pairs upstream of the transcription start site and the binding amount was decreased after treatment with LPS. The dual-luciferase reporter assay indicated that NFATc1 was a direct target of KLF15. In addition, we found that in vitro treatment with dexamethasone induced a decrease of NFATc1 expression in podocytes and was abrogated by knockdown of KLF15. Hence, our results identify the critical role of the KLF15-NFATc1 axis in podocyte injury and loss, which may be involved in mediating the salutary effects of dexamethasone in podocytes.


Assuntos
Glucocorticoides/uso terapêutico , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição NFATC/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Dexametasona/farmacologia , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Técnicas de Silenciamento de Genes , Inativação Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Glucose/toxicidade , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Biológicos , Transdução de Sinais
14.
Ultrasonics ; 108: 106198, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32590261

RESUMO

Contrast-enhanced ultrasound (CEUS) is widely applied in cancer diagnosis clinically. However, the gas-filled contrast agents are unstable in the blood and exhibit shorter imaging time, which limit their clinical use. In this study, a diagnostic nanoparticle system was developed for dual-mode imaging (ultrasound and fluorescence), which after encapsulation with doxorubicin (DOX) demonstrated simultaneous therapeutic function towards cancer treatment. Thus, calcium carbonate (CaCO3) nanoparticles were encapsulated with doxorubicin (DOX) to obtain CaCO3-DOX. Under acidic conditions, it produced carbon dioxide (CO2) to enhance ultrasound imaging and increase the release of DOX. After intravenously injecting CaCO3-DOX to tumor-bearing mice, in the presence of an ultrasound field, CO2bubbles were sufficiently generated at the tumor tissues for echogenic reflectivity. Also, the indocyanine green (ICG) was encapsulated into CaCO3 nanoparticles, to further detect the tumor with fluorescence. The resultant theranostic nanoparticle system exhibited therapeutic efficacy towards tumour-bearing mice. Overall, this investigation provides an attractive strategy for dual-mode cancer diagnostics.


Assuntos
Carbonato de Cálcio/farmacologia , Doxorrubicina/farmacologia , Imagem Multimodal , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Ultrassonografia/métodos , Animais , Carbonato de Cálcio/química , Dióxido de Carbono/metabolismo , Linhagem Celular Tumoral , Meios de Contraste , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Fluorescência , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Microambiente Tumoral
15.
Mol Biol (Mosk) ; 54(2): 293-299, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392199

RESUMO

Novel treatments for various types of malignant diseases are warranted. In this study, we evaluated JAK2 inhibitors (Janus kinase 2) for suppressing the growth of malignant neuroblastoma and glioblastoma cells as well as breast and non-small cell lung cancers. Neuroblastoma and glioblastoma cells are the most sensitive to the JAK2 inhibitor AG490. A study of the relative expression of receptors that can activate JAK2 suggests that cell line sensitivity to AG490 may be mediated by IL6-R, IL11-R and/or CSF1-R. AG490 enhances the effect of doxorubicin on neuroblastoma cells. Our findings suggest the possible relevance of JAK2 inhibitors for neuroblastoma therapy, especially in combination with doxorubicin.


Assuntos
Doxorrubicina/farmacologia , Janus Quinase 2/antagonistas & inibidores , Neuroblastoma/patologia , Ciclo Celular , Linhagem Celular Tumoral , Humanos , Janus Quinase 2/metabolismo , Fosforilação , Transdução de Sinais , Tirfostinas/farmacologia
16.
Int J Nanomedicine ; 15: 3235-3250, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440121

RESUMO

Background: Metal-organic frameworks (MOFs) have attracted intensive research interest in the biomedical field because of their unique properties. However, in order to realize the high loading capacity and therapeutic efficacy, it is still urgent to develop a multifunctional MOFs-based nanoplatform. Materials and Methods: Herein, a pH/near-infrared (NIR) dual-responsive drug delivery system based on zeolitic imidazolate framework-8 (ZIF-8) is constructed for synergistic chemo-photothermal therapy and dual-modal magnetic resonance (MR)/photoacoustic (PA) imaging. The doxorubicin hydrochloride (DOX) is embedded into ZIF-8 through one-pot method, and the resultant ZIF-8/DOX is then successively modified with polydopamine, Mn ions and poly(ethylene glycol). The obtained ZIF-8/DMPP is systematically characterized, and both its in vitro and in vivo biological effects are evaluated in detail. Results: The ZIF-8/DMPP possesses a high drug-loading content of 18.9% and displays appropriate size and morphology. The pH-dependent degradation and drug release behavior of prepared ZIF-8/DMPP are confirmed. Importantly, the results demonstrate that the photothermal effect of ZIF-8/DMPP under NIR laser irradiation can significantly accelerate its drug releasing rate, further improving the intracellular drug concentrations. Thereafter, the augmented chemotherapeutic efficiency by photothermal effect against cancer cells is verified both in vitro and in vivo. Besides, the favorable MR and PA imaging capacity of ZIF-8/DMPP is also evidenced on the tumor model. Conclusion: Taken together, the surface engineering of ZIF-8-based nanocarrier in this work offers a promising strategy for the multifunctional MOFs-based drug delivery system.


Assuntos
Portadores de Fármacos/química , Hipertermia Induzida , Imageamento Tridimensional , Raios Infravermelhos , Estruturas Metalorgânicas/química , Nanopartículas/química , Nanotecnologia/métodos , Fototerapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Indóis/química , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Polímeros/química , Temperatura
17.
Int J Nanomedicine ; 15: 2873-2884, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368059

RESUMO

Purpose: The primary goal of the present study was to design doxorubicin (DOX)-loaded superparamagnetic iron oxide (SPIO) nanoparticles (NPs) coated with mesenchymal stem cell (MSC) membranes and explore their effect on colon cancer in vitro and in vivo. Methods: DOX-SPIO NPs were coated with MSC membranes using an extruder, and the morphological characteristics of MSC membrane-camouflaged nanodrug (DOX-SPIO@MSCs) evaluated by transmission electron microscopy (TEM) and NP-tracking analysis. Drug loading and pH response were assessed by UV spectrophotometry. Intracellular colocalization was analyzed using NP-treated MC38 cells stained with 3,3'-dioctadecyloxacarbocyanine perchlorate and Hoechst 33342. Cellular uptake was analyzed using an inverted fluorescence microscope and flow cytometry and cytotoxicity evaluated by cell counting kit-8 assay. Biological compatibility was assessed by hemolysis analysis, immunoactivation test and leukocyte uptake experiments. Furthermore, intravenous injection of chemotherapy drugs into MC38 tumor-bearing C57BL/6 mice was used to study anti-tumor effects. Results: Typical core-shell NP structures were observed by TEM. Particle size remained stable in fetal bovine serum and phosphate-buffered saline (PBS). Compared with DOX-SPIO, DOX-SPIO@MSCs improved cellular uptake efficiency, enhanced anti-tumor effects, and reduced the immune system response. Animal experiments demonstrated that DOX-SPIO@MSCs enhanced tumor treatment efficacy while reducing systemic side effects. Conclusion: Our experimental results demonstrate that DOX-SPIO@MSCs are a promising targeted nanocarrier for application in treatment of colon cancer.


Assuntos
Membrana Celular/transplante , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Células-Tronco Mesenquimais/citologia , Nanopartículas/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Feminino , Compostos Férricos/química , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Nanopartículas/administração & dosagem , Tamanho da Partícula , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Gene ; 753: 144807, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32461017

RESUMO

Mitochondrial transcription factor A (TFAM), which is required for mitochondrial DNA (mtDNA) transcription, has been linked to metabolic changes that contribute to tumorigenesis and chemoresistance. In this work, we investigated the expression pattern and role of TFAM in hepatocellular carcinoma (HCC). TFAM expression level is similar in 18 out of 20 paired normal liver and HCC tissues with only 2 HCC tissues showing 1.8-fold increase in TFAM. Similar phenomenon was observed in HCC cell lines compared to normal liver lines. Interestingly, TFAM expression is upregulated in resistant HCC cells regardless of the differential TFAM expression level in their parental lines and mechanism of resistance. TFAM depletion led to inhibition of growth and survival but not migration, and sensitization to doxorubicin and sorafenib treatment, through AMPK activation, reduction of nucleoside triphosphates and mitochondrial respiration in HCC cells. In addition, we demonstrated that resistant HCC cell lines were more sensitive to TFAM inhibition than parental lines, and this might be due to the increased mitochondrial biogenesis in resistant HCC cell lines. Our work reveals the preferential role of TFAM in HCC cell response to standard of care drugs, which suggests a potential sensitizing therapeutic target for HCC treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ligação a DNA/deficiência , Doxorrubicina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias/metabolismo , Proteínas Mitocondriais/deficiência , Sorafenibe/farmacologia , Fatores de Transcrição/deficiência , Proteínas Quinases Ativadas por AMP/genética , Adulto , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação para Cima
19.
Phytomedicine ; 70: 153215, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32388040

RESUMO

BACKGROUND: Recalcitrant cancers appear as a major obstacle to chemotherapy, prompting scientists to intensify the search for novel drugs to tackle the cell lines expressing multi-drug resistant (MDR) phenotypes. PURPOSE: The purpose of this study was to evaluate the antiproliferative potential of a ferrulic acid derivative, 8,8-bis-(dihydroconiferyl)-diferulate (DHCF2) on a panel of 18 cancer cell lines, including various sensitive and drug-resistant phenotypes, belonging to human and animals. The mode of induction of cell death by this compound was further studied. METHODS: The antiproliferative activity, autophagy, ferroptotic and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the activity of caspases. Cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA) were assessed by flow cytometry. RESULTS: DHCF2 demonstrated impressive cytotoxic effects towards the 18 cancer cell lines tested, with IC50 values all below 6.5 µM. The obtained IC50 values were in the range of 1.17 µM (towards CCRF-CEM leukemia cells) to 6.34 µM (towards drug-resistant HCT116 p53-/- human colon adenocarcinoma cells) for DHCF2 and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against multidrug-resistant CEM/ADR5000 leukemia cells) for the reference drug, doxorubicin. DHCF2 had IC50 values lower than those of doxorubicin, against CEM/ADR5000 cells and on some melanoma cell lines, such as MaMel-80a cells, Mel-2a cells, MV3 cells and SKMel-505 cells. DHCF2 induced autophagy as well as apoptosis in CCRF-CEM cells though caspases activation, MMP alteration and increase of ROS production. CONCLUSION: The studied diferulic acid, DHCF2, is a promising antiproliferative compound. It deserves further indepth investigations with the ultimate aim to develop a novel drug to fight cancer drug resistance.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade
20.
Toxicol Appl Pharmacol ; 399: 115038, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32417440

RESUMO

The cardiotoxicity caused by doxorubicin and extravasation injury caused by anthracyclines is reduced by the clinically approved bisdioxopiperazine drug dexrazoxane. Dexrazoxane is a rings-closed analog of EDTA and is hydrolyzed in vivo to a form that strongly binds iron. Its protective effects were originally thought to be due to the ability of its metabolite to remove iron from the iron-doxorubicin complex, thereby preventing oxygen radical damage to cellular components. More recently it has been suggested that dexrazoxane may exert its protective effects by inhibiting topoisomerase IIß in the heart and inducing a reduction in its protein levels through induction of proteasomal degradation. The ability of dexrazoxane, other bisdioxopiperazines, and mitindomide to protect against doxorubicin-induced damage was determined in primary neonatal rat myocytes. This QSAR study showed that the protection that a series of bisdioxopiperazine analogs of dexrazoxane and the bisimide mitindomide offered against doxorubicin-induced myocyte damage was highly correlated with the ability of these compounds to catalytically inhibit the decatenation activity of topoisomerase II. The structural features of the dexrazoxane analogs that contribute to the binding and inhibition of topoisomerase II have been identified. These results suggest that the inhibition of topoisomerase II in myocytes by dexrazoxane is central to its role in its activity as an anthracycline cardioprotective agent. Additionally, sequence identity analysis of the amino acids surrounding the dexrazoxane binding site showed extremely high identity, not only between both invertebrate topoisomerase II isoforms, but also with yeast topoisomerase II as well.


Assuntos
Cardiotônicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Dexrazoxano/farmacologia , Doxorrubicina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antraciclinas/farmacologia , Feminino , Isoindóis/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Sprague-Dawley
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