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1.
Biochim Biophys Acta Mol Cell Res ; 1867(5): 118676, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32044386

RESUMO

In egress routes of malignancy, cancer cells are constantly subjected to shear stress imposed by blood/lymph flow. Increasing evidence points toward the regulatory roles of shear stress in tumor cell adhesion and motility. Although it is known that integrin endocytic trafficking governs focal adhesion (FA) turnover and cell migration, the effect and biological consequences of low shear stress (LSS) on integrin trafficking remain unclear. Here, we identified the critical role of integrin ß1 trafficking and caveolin-1 (Cav-1) mediated endocytosis in LSS-induced cell directional migration. LSS altered the distribution of integrin ß1 in MDA-MB-231 cells and significantly promoted its internalization and recycling, which in turn facilitated FA turnover and directional cell migration. Furthermore, LSS induced cytoskeleton remodeling, which was required for internalization of integrin ß1. LSS down-regulated the acetylation level of microtubules (MTs) via activating ROCK/HDAC6 pathway, resulting in elevation of MTs dynamics, Cav-1 motility, and Cav-1-dependent integrin ß1 recycling. We also showed that high HDAC6 expression was a ROCK-dependent prognostic factor, which was correlated with poor outcomes in breast cancer patients. Taken together, these results defined a novel mechanism by which LSS enhanced integrin ß1 trafficking via actin cytoskeleton remodeling and ROCK/HDAC6 mediated deacetylation of MTs, thereby promoting FAs turnover and directional cell migration.

2.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165625, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785406

RESUMO

One of the hallmarks of cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast cancer treatment delivery systems.

3.
Adv Healthc Mater ; 9(1): e1901187, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31800164

RESUMO

Highly efficient and stimulus-responsive nanomedicines for cancer treatment are currently receiving tremendous attention. In this study, an acid-triggered charge-reversible graphene-based all-in-one nanocomplex is appropriately designed by surface modification with multilayer polymers and simultaneous co-transportation of photosensitizer indocyanine green (ICG) and oligonucleotide inhibitor of miR-21 (miR-21i) to achieve highly efficient genetic phototherapy in a controlled manner. The nanocomplex (denoted as GPCP/miR-21i/ICG) effectively protects miR-21i from degradation and exhibits excellent photothermal/photochemical reactive oxygen species (ROS) generation as well as fluorescence imaging ability. The cargoes ICG and miR-21i can significantly be released at acidic pH compared with normal physiological medium and escaped from endosomes/lysosomes due to the acid-triggered charge reversal effect. Typically, the released miR-21i downregulate the endogenous miR-21 and result in the upregulation of the target proteins PTEN and Bax, thus increasing the phototherapeutic efficiency of ICG. High in vivo anticancer efficiency against the MDA-MB-231 triple-negative breast cancer (TNBC) model is obtained due to the combination of genetic regulation of miR-21i and the photokilling effect of ICG. This work highlights the great potential of this smart nanocomplex as an attractive modality of gene-photo combined treatment of cancer, especially for intractable TNBC.

4.
J Control Release ; 317: 43-56, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31758970

RESUMO

Myeloid-derived suppressor cells(MDSCs)are one of the most important immunosuppressive cells in tumor microenvironment, which also promote the development and progression of tumor cells. Nevertheless, due to the different distribution features of MDSCs and tumor cells, selective elimination of MDSCs and tumor cells in tumor microenvironment remain a great challenge. Here we have designed a dual-pH-sensitivity conjugated micelle system (PAH/RGX-104@PDM/PTX) that could deliver liver-X nuclear receptor (LXR) agonist RGX-104 and paclitaxel (PTX) to the perivascular region and tumor cells, respectively. Upon arrival at the acidic tumor microenvironment, the PAH/RGX-104@PDM/PTX undergo structure disintegration and capacitate coinstantaneous release of RGX-104 in the perivascular regions, leaving the intact PTX containing micelles PDM/PTX for tumor deep penetration. The released RGX-104 can be preferentially taken up by leukocytes, endothelial cells and macrophages which are nicely enriched in perivascular regions to active the LXR, and further reduces immunosuppressive MDSC levels. The remained small micelles carrying PTX enable deep tumor penetration as well as rapid specific drug release in the endosomal/lysosomal to kill tumor cells. PAH/RGX-104@PDM/PTX exhibits superior tumor accumulation as well as tumor penetration, and suppresses 74.88% in vivo tumor growth. More importantly, PAH/RGX-104@PDM/PTX has significantly alleviated tumor immunosuppression by eliminating MDSCs and increasing cytotoxic T lymphocytes infiltration. Our studies suggest that the dual-pH-sensitive codelivery nanocarrier not only cause apoptosis of cancer cells but also regulate the tumor immune environment to ultimately enhance the antitumor effect of CTLs through MDSCs depletion.

5.
ACS Appl Mater Interfaces ; 11(47): 43865-43878, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31684723

RESUMO

To realize precise tumor therapy, a versatile oncotherapy nanoplatform integrating both diagnostic and therapeutic functions is necessary. Herein, we fabricated a hybrid micelle (HM) utilizing two amphiphilic diblock copolymers, polyethylenimine-polycaprolactone (PEI-PCL) and diethylenetriaminepentaacetic acid gadolinium(III)  (Gd-DTPA)-conjugated polyethyleneglycol-polycaprolactone (Gd-PEG-PCL), to codeliver the small-molecule chemotherapy drugs doxorubicin (Dox) and microRNA-34a (miR-34a), denoted as Gd-HM-Dox/34a. Conjugating Gd-DTPA on the surface of hybrid micelles, leading the relaxation rate of Gd-DTPA increased more than 1.4 times (13.6 mM-1 S-1). Furthermore, hybrid micelles enhanced the ability of miR-34a to escape from lysosomes/endosomes and Dox release to the nucleus. In addition, the released miR-34a subsequently downregulates Bcl-2, cyclin D1, CDK6, and Bax expression and inhibits proliferation and migration of MDA-MB-231 breast cancer cells. Moreover, the suitable micelle size improved the penetration of Dox into three-dimensional (3D) multicellular spheroids compared with Gd-HM-Dox and Free Dox, generating efficient cell killing in the 3D multicellular spheroids. Furthermore, the Gd-HM-Dox/34a exhibited augmented accumulation in the tumor tissue, which improved the magnetic resonance (MR) imaging contrast of solid tumors and enhanced the combined efficiency of chemotherapeutic drugs Dox and therapeutic gene miR-34a in suppressing tumor growth on MDA-MB-231 tumor-bearing mice. Therefore, we established a hybrid micelle to offer a promising theranostic approach that inhibits tumor growth and enhances MR imaging.

6.
Bioconjug Chem ; 30(10): 2675-2683, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31560538

RESUMO

Exosomes have attracted tremendous attention due to their important role in physiology, pathology, and oncology, as well as promising potential in biomedical applications. Although great efforts have been dedicated to investigating their biological properties and applications as natural cancer drug-delivery systems, the systemic biodistribution of exosomes remains underexplored. In addition, exosome-based drug delivery is inevitably hindered by the robust liver clearance, leading to suboptimal tumor retention and therapeutic efficiency. In this study, we report one of the first examples using in vivo positron emission tomography (PET) for noninvasive monitoring of copper-64 (64Cu)-radiolabeled polyethylene glycol (PEG)-modified exosomes, achieving excellent imaging quality and quantitative measurement of blood residence and tumor retention. PEGylation not only endowed exosomes with a superior pharmacokinetic profile and great accumulation in the tumor versus traditionally reported native exosomes but also reduced premature hepatic sequestration and clearance of exosomes, findings that promise enhanced therapeutic delivery efficacy and safety in future studies. More importantly, this study provides important guidelines about surface engineering, radiochemistry, and molecular imaging in obtaining accurate and quantitative biodistribution information on exosomes, which may benefit future exploration in the realm of exosomes.

7.
Theranostics ; 9(20): 5784-5796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534519

RESUMO

Background & Aims: The use of antisense oligonucleotide-based nanosystems for the detection and regulation of tumor-related gene expression is thought to be a promising approach for cancer diagnostics and therapies. Herein, we report that a cubic-shaped iron oxide nanoparticle (IONC) core nanobeacon is capable of delivering an HSP90α mRNA-specific molecular beacon (HSP90-MB) into living cells and enhancing T 2-weighted MR imaging in a tumor model. Methods: The nanobeacons were built with IONC, generation 4 poly(amidoamine) dendrimer (G4 PAMAM), Pluronic P123 (P123) and HSP90-MB labeled with a quencher (BHQ1) and a fluorophore (Alexa Fluor 488). Results: After internalization by malignant cells overexpressing HSP90α, the fluorescence of the nanobeacon was recovered, thus distinguishing cancer cells from normal cells. Meanwhile, MB-mRNA hybridization led to enzyme activity that degraded DNA/RNA hybrids and resulted in downregulation of HSP90α at both the mRNA and protein levels. Furthermore, the T 2-weighted MR imaging ability of the nanobeacons was increased after PAMAM and P123 modification, which exhibited good biocompatibility and hemocompatibility. Conclusions: The nanobeacons show promise for applicability to tumor-related mRNA detection, regulation and multiscale imaging in the fields of cancer diagnostics and therapeutics.

9.
Biophys J ; 116(10): 1803-1814, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31076101

RESUMO

Tumor cells disseminate to distant organs mainly through blood circulation in which they experience considerable levels of fluid shear stress. However, the effects of hemodynamic shear stress on biophysical properties and functions of circulating tumor cells (CTCs) in suspension are not fully understood. In this study, we found that the majority of suspended breast tumor cells could be eliminated by fluid shear stress, whereas cancer stem cells held survival advantages over conventional cancer cells. Compared to untreated cells, tumor cells surviving shear stress exhibited unique biophysical properties: 1) cell adhesion was significantly retarded, 2) these cells exhibited elongated morphology and enhanced spreading and expressed genes related to epithelial-mesenchymal transition or hybrid phenotype, and 3) surviving tumor cells showed reduced F-actin assembly and stiffness. Importantly, inhibiting actomyosin activity promoted the survival of suspended tumor cells in fluid shear stress, whereas activating actomyosin suppressed cell survival, which might be explained by the up- and downregulation of the antiapoptosis genes. Soft surviving tumor cells held survival advantages in shear flow and higher resistance to chemotherapy. Inhibiting actomyosin activity in untreated cells enhanced chemoresistance, whereas activating actomyosin in surviving tumor cells suppressed this ability. These findings might be associated with the corresponding changes in the genes related to multidrug resistance. In summary, these data demonstrate that hemodynamic shear stress significantly influences biophysical properties and functions of suspended tumor cells. Our study unveils the regulatory roles of actomyosin in the survival and drug resistance of suspended tumor cells in hemodynamic shear flow, which suggest the importance of fluid shear stress and actomyosin activity in tumor metastasis. These findings may reveal a new, to our knowledge, mechanism by which CTCs are able to survive hemodynamic shear stress and chemotherapy and may offer a new potential strategy to target CTCs in shear flow and combat chemoresistance through actomyosin.

10.
Biomaterials ; 205: 106-119, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30913486

RESUMO

Currently, photoimmunotherapy based on a theranostic nanoplatform emerges as a promising modality in advanced cancer therapy. In this study, a new type of versatile nanoassemblies (denoted as PC@GCpD(Gd)) was rationally designed by integrating the polydopamine stabilized graphene quantum dots (GQD)-photosensitizer nanocomposites (denoted as GCpD), immunostimulatory polycationic polymer/CpG oligodeoxynucleotide (CpG ODN) nanoparticles (denoted as PC) and Gd3+/Cy3 imaging probes for dual magnetic resonance/fluorescence imaging-guided photoimmunotherapy. PC@GCpD(Gd) effectively killed the tumor cells through the amplified photothermal and photodynamic effects mediated by GCpD, and contemporaneously delivered CpG ODN to the targeted endosomal Toll-like receptor 9 (TLR9) to continuously stimulate the secretion of proinflammatory cytokines and the maturation of dendritic cells, thereby resulting in the activation and infiltration of T lymphocytes. As a result, PC@GCpD(Gd) achieved robust inhibition efficiency to almost completely suppress the EMT6 murine mammary cancer model under laser irradiation, implying the superior synergy of combined photoimmunotherapy. Moreover, the in vivo delivery and biodistribution of PC@GCpD(Gd) could be tracked using the high-quality bimodal magnetic resonance imaging/fluorescence imaging. This study highlighted the potent prospect of hybrid PC@GCpD(Gd) nanoassemblies for precise cancer photoimmunotherapy with a cascading effect.

11.
Acta Biomater ; 88: 86-101, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771534

RESUMO

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM stiffness in cancer is well known. However, the biomechanical behavior of tumor cells and the underlying mechanotransduction pathways remain unclear. Here, we used polyacrylamide (PAA) substrates to simulate tissue stiffness at different progress stages of breast cancer in vitro, and we observed that moderate substrate stiffness promoted breast cancer cell motility. The substrate stiffness directly activated integrin ß1 and focal adhesion kinase (FAK), which accelerate focal adhesion (FA) maturation and induce the downstream cascades of intracellular signals of the RhoA/ROCK pathway. Interestingly, the differential regulatory mechanism between two ROCK isoforms (ROCK1 and ROCK2) in cell motility and mechanotransduction was clearly identified. ROCK1 phosphorylated the myosin regulatory light chain (MRLC) and facilitated the generation of traction force, while ROCK2 phosphorylated cofilin and regulated the cytoskeletal remodeling by suppressing F-actin depolymerization. The ROCK isoforms differentially regulated the pathways of RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin in a coordinate fashion to modulate breast cancer cell motility in a substrate stiffness-dependent manner through integrin ß1-activated FAK signaling. Our findings provide new insights into the mechanisms of matrix mechanical property-induced cancer cell migration and malignant behaviors. STATEMENT OF SIGNIFICANCE: Here, we examined the relationship between substrate stiffness and tumor cellular motility by using polyacrylamide (PAA) substrates to simulate the stages in vivo of breast cancer. The results elucidated the different regulatory roles between the two ROCK isoforms in cell motility and demonstrated that stiff substrate (38 kPa) mediated RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin pathways through integrin ß1-FAK activation and eventually promoted directional migration. Our discoveries would have significant implications in the understanding of the interaction between cancer cells and tumor microenvironments, and hence, it might provide new insights into the metastasis inhibition, which could be an adjuvant way of cancer therapy.

12.
Mol Pharm ; 16(3): 1367-1384, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776896

RESUMO

A promising approach toward cancer therapy is expected to integrate imaging and therapeutic agents into a versatile nanocarrier for achieving improved antitumor efficacy and reducing the side effects of conventional chemotherapy. Herein, we designed a poly(d,l-lactic- co-glycolic acid) (PLGA)-based theranostic nanoplatform using the double emulsion solvent evaporation method (W/O/W), which is associated with bovine serum albumin (BSA) modifications, to codeliver indocyanine green (ICG), a widely used near-infrared (NIR) dye, and doxorubicin (Dox), a chemotherapeutic drug, for dual-modality imaging-guided chemo-photothermal combination cancer therapy. The resultant ICG/Dox co-loaded hybrid PLGA nanoparticles (denoted as IDPNs) had a diameter of around 200 nm and exhibited excellent monodispersity, fluorescence/size stability, and biocompatibility. It was confirmed that IDPNs displayed a photothermal effect and that the heat induced faster release of Dox, which led to enhanced drug accumulation in cells and was followed by their efficient escape from the lysosomes into the cytoplasm and drug diffusion into the nucleus, resulting in a chemo-photothermal combinatorial therapeutic effect in vitro. Moreover, the IDPNs exhibited a high ability to accumulate in tumor tissue, owing to the enhanced permeability and retention (EPR) effect, and could realize real-time fluorescence/photoacoustic imaging of solid tumors with a high spatial resolution. In addition, the exposure of tumor regions to NIR irradiation could enhance the tumor penetration ability of IDPNs, almost eradicating subcutaneous tumors. In addition, the inhibition rate of IDPNs used in combination with laser irradiation against EMT-6 tumors in tumor-bearing nude mice (chemo-photothermal therapy) was approximately 95.6%, which was much higher than that for chemo- or photothermal treatment alone. Our study validated the fact that the use of well-defined IDPNs with NIR laser treatment could be a promising strategy for the early diagnosis and passive tumor-targeted chemo-photothermal therapy for cancer.


Assuntos
Terapia Combinada/métodos , Doxorrubicina/química , Verde de Indocianina/química , Raios Infravermelhos/uso terapêutico , Nanopartículas/química , Neoplasias/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Soroalbumina Bovina/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Doxorrubicina/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Temperatura Alta , Verde de Indocianina/efeitos adversos , Verde de Indocianina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Nanopartículas/efeitos adversos , Nanopartículas/metabolismo , Imagem Óptica , Fototerapia/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/efeitos adversos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Soroalbumina Bovina/efeitos adversos , Soroalbumina Bovina/metabolismo , Distribuição Tecidual , Resultado do Tratamento
13.
Acta Biomater ; 89: 1-13, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30797106

RESUMO

Recently, drug delivery systems based on nanotechnology have received great attention in cancer therapeutics and diagnostics since they can not only improve the treatment efficacy but also reduce the side effects. Among them, mesoporous silica nanoparticles (MSNs) with large surface area, high pore volume, tunable pore size, abundant surface chemistry, and acceptable biocompatibility exhibit unique advantages and are considered as promising candidates for cancer diagnosis and therapy. In this review, we update the recent progress on MSN-based systems for cancer treatment purposes. We also discuss the drug loading mechanism of MSNs, stimuli-responsive drug release, and surface modification strategies for improving biocompatibility, and targeting functionalities. STATEMENT OF SIGNIFICANCE: The development of MSN-based delivery systems that can be used in both diagnosis and treatment of cancer has attracted tremendous interest in the past decade. MSN-based delivery systems can improve therapeutic efficacy and reduce cytotoxicity to normal tissue. To further improve the in vivo properties of MSNs and potential translation to the clinics, it is critical to design MSNs with appropriate surface engineering and desirable cancer targeting. This review is intended to provide the readers a comprehensive background of the vast literature till date on silica-based drug delivery systems, and to inspire further innovations in silica nanomedicine in the future.

14.
Biochem Biophys Res Commun ; 510(2): 219-223, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30685085

RESUMO

Micro-environmental regulation of cancer cell malignancy is one of the most basic cancer life phenomena. However, the study of cellular response to microenvironment has been long focused on signal processes mediated by various chemical factors and their receptors, the study of mechanical forces, another key environmental factor, has been less studied. In recent years, more and more attention has been paid to the physiological and pathological significance of mechanical microenvironment. However, it is still not clear how cells perceive environmental changes and the signal pathways that regulate cell physiological activities. In this study, we identified that low shear stress (LSS) significantly promoted breast cancer cell proliferation. The proliferation was closely associated with mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) and Yes-associated protein (YAP). Inhibition of ERK or YAP both abolished the LSS-induced proliferation activity of cancer cells. LSS induced ERK phosphorylation and YAP activations, which suggested the involvement of ERK and YAP under LSS treatment. Under LSS, ERK inhibitor U0126 decreased both active YAP and ERK expressions, while YAP inhibitor verteporfin failed to decrease ERK phosphorylation. Further study confirmed that ERK translocated to nucleus which showed an active state of ERK in LSS-treated group. LSS with verteporfin group showed no differences with LSS-treated group which confirmed ERK and YAP an upstream-downstream cascade. The above results demonstrated that LSS can promote breast cancer cell proliferation through ERK-YAP activation. These results not only highlight a new means of understanding mechanical transmission to cytoplasm mechanisms but also serve as a new basis for developing drug delivery systems for breast cancer treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Núcleo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfoproteínas/metabolismo , Transporte Ativo do Núcleo Celular , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Citoplasma/metabolismo , Feminino , Humanos , Fosforilação , Resistência ao Cisalhamento , Estresse Mecânico , Fatores de Transcrição
15.
Medicine (Baltimore) ; 98(2): e14000, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30633187

RESUMO

RATIONALE: Cardiac lymphangioma is a rare disease. Until now, there have been only a few cases of cardiac lymphangioma reported in the literature. PATIENT CONCERNS: We report the case of a 57-year-old female patient with cardiac lymphangioma from atrial septum. DIAGNOSIS: Color Doppler echocardiography was performed, which revealed a tumor occupying a large amount of space in the left and right atrium. INTERVENTIONS: The patient underwent thoracoscopic cardiac tumor resection under general anesthesia according to the procedure used for benign tumors. OUTCOMES: The patient recovered completely and was discharged home. Follow-up color Doppler echocardiography scans obtained from 6 months to 2 years after the operation showed no recurrent mass. LESSONS: Once the tumor is detected, surgical treatment should be implemented as soon as possible.


Assuntos
Neoplasias Cardíacas/diagnóstico , Linfangioma/diagnóstico , Ecocardiografia Doppler , Feminino , Átrios do Coração/patologia , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/cirurgia , Humanos , Linfangioma/diagnóstico por imagem , Linfangioma/cirurgia , Pessoa de Meia-Idade
16.
J Cell Physiol ; 234(4): 3730-3743, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30171601

RESUMO

Circulating tumor cells (CTCs) need to acquire resistance to anoikis to survive after they experience fluid shear stress in the circulatory and lymphatic systems. However, the mechanism by which tumor cells resist anoikis under shear stress conditions remains unknown. Here, we found that the application of low shear stress (LSS; 2 dyn/cm2 ) to human breast carcinoma cells (MDA-MB-231) resulted in increased anoikis resistance when tumor cells were grown under anchorage-independent conditions. Caveolin-1 (Cav-1), the major component of plasma membrane caveolae, was overexpressed in LSS-treated cells and prevented tumor cells from anoikis, while depletion of Cav-1 restored sensitivity to anoikis. LSS-induced dissociation of Cav-1-Fas inhibited formation of the death-inducing signaling complex, caspase-8 activation, and rendered tumor cells resistant to anoikis. Likewise, LSS blocked the mitochondrial pathway through promotion of integrin ß1-focal adhesion kinase-mediated multicellular aggregation and suppression of truncated BID translocation mediated crosstalk between the extrinsic and intrinsic apoptotic pathways. Our findings provide insights into the mechanisms by which LSS induces anoikis resistance in breast carcinoma cells through inhibition of Cav-1-dependent extrinsic and intrinsic apoptotic pathways, and serves as a potential therapeutic target for CTCs and metastatic breast cancer.

17.
Environ Pollut ; 242(Pt A): 914-921, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30373036

RESUMO

Bisphenol A (BPA) exposure receives great ecotoxicological concern. However, gaps in knowledge, such as metabolism of BPA and inconsistent reports on reproductive toxicity, still exist. In this study, a marine fish model (Oryzias melastigma) was exposed to serial concentrations of BPA throughout its whole life cycle. The level of BPA-glucuronide (BPAG) dramatically increased throughout the embryonic stage since 4 dpf. Accordingly, the mRNA level and enzymatic activity of UDP-glucuronosyltransferases (UGTs) increased across the embryonic stage. The mRNA level of UGT2 subtype rather than UGT1 or UGT5 showed a concentration dependent response to BPA exposure. BPA exposure led to the morphological disruption of the chorion and villi as shown by scanning electron microscopy; however, the hatchability was not significantly influenced after exposure. Newly hatching larvae were continuously exposed to BPA for 120 days. Lower mRNA levels of hormone metabolism-related genes, decreased ratio of E2/T, slower ovary development and decreased egg production confirmed the inhibitory effect of BPA on reproduction. Overall, our results showed the conjugation of BPA into BPAG by UGT2 at the embryonic stage and convinced the reproductive toxicity from multiple levels after whole life exposure to BPA.


Assuntos
Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Testes de Toxicidade Crônica , Poluentes Químicos da Água/toxicidade , Animais , Compostos Benzidrílicos/metabolismo , Feminino , Glucuronídeos , Glucuronosiltransferase , Larva/efeitos dos fármacos , Oryzias/embriologia , Fenóis/metabolismo , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/metabolismo
19.
J Membr Biol ; 251(5-6): 681-693, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30094474

RESUMO

In this paper, the membrane electroporation induced by the terahertz electric field is simulated by means of the molecular dynamics method. The influences of the waveform and frequency of the applied terahertz electric field on the electroporation and the unique features of the process of the electroporation with the applied terahertz electric field are given. It shows that whether the electroporation can happen depends on the waveform of the applied terahertz electric field when the magnitude is not large enough. No pore appears if the terahertz electric field direction periodically reverses, and dipole moments of the interfacial water and the bulk water keep reversing. The nm-scale single pore forms with the applied terahertz trapezoidal electric field. It is found that the average pore formation time is strongly influenced by the terahertz electric field frequency. An abnormal variation region that shows decline exists on the correlation curve of the average pore formation time and the trapezoidal electric field frequency, whereas the overall trend of the curve is increasing. The decrease of the water oriented polarization degree results in the increase of the electroporation time, and the abnormal variation region appearance may be related to the drastic change of average water hydrogen bond number that is resulted from the resonance of water hydrogen bond network and the applied electric field. Compared to the nanosecond electric pulse and constant electric field, the numbers of the water protrusions and the water bridges are smaller and the pore formation time is relatively longer with the applied terahertz electric field.


Assuntos
Campos Eletromagnéticos , Eletroporação/métodos , Bicamadas Lipídicas/química , Ligações de Hidrogênio , Simulação de Dinâmica Molecular
20.
Biomater Sci ; 6(9): 2426-2439, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30040100

RESUMO

The efficacy of cancer chemotherapy can be generally restrained by the multiple drug resistance (MDR) of tumors, which is typically attributed to the upregulation of ATP-binding cassette (ABC) transporter proteins, such as P-glycoprotein (P-gp). There is an urgent need to present innovative strategies to reverse MDR and enhance the therapeutic efficacy of chemotherapeutic agents in biomedical applications. Here, we report a novel nanosystem of charge-reversal-functionalized PLGA nanobubbles (denoted as Dox-NBs/PPP/P-gp shRNA) for the co-delivery of Dox and P-gp shRNA for the reversal of drug resistance and for ultrasonic-imaging-guided tumor therapy. 1H NMR, FT-IR, SEM, DLS, and UV-vis spectroscopy characterizations were conducted to determine the structure, morphology, and composition of the as-prepared nanobubbles. Dox-NBs/PPP/P-gp shRNA exhibited an average diameter of about 300 nm with good dispersity, biocompatibility, and pH-responsive release properties through the charge-reversal process. The in vitro experiments showed that Dox-NBs/PPP/P-gp shRNA nanobubbles could co-deliver Dox and P-gp shRNA into tumor cells and could effectively suppress P-gp expression, leading to enhanced overall therapeutic effects against MCF-7/MDR cells by restraining the drug efflux. An in vivo antitumor assay revealed an approximately 65% inhibition rate of Dox-NBs/PPP/P-gp shRNA against MCF-7/ADR tumors in tumor-bearing nude mice. Both the in vitro and in vivo toxicity results indicated the Dox-NBs/PPP/P-gp shRNA are highly biocompatible with reducing side-effects and have negligible systemic toxicity in the in vivo therapy of resistant cancers by combining with a chemotherapeutic agent and P-gp knockdown. Furthermore, the in vivo imaging data substantiated that the functionalized nanobubbles could be used as an efficient contrast agent for the ultrasonic imaging of solid tumors. This works highlights the great potential of Dox-NBs/PPP/P-gp shRNA nanobubbles for enhanced imaging-guided combination therapy for overcoming MDR.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Nanoestruturas/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Anidridos Citracônicos/administração & dosagem , Anidridos Citracônicos/química , Terapia Combinada , Doxorrubicina/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Polímeros/administração & dosagem , Polímeros/química , RNA Interferente Pequeno/química , Nanomedicina Teranóstica , Carga Tumoral/efeitos dos fármacos , Ultrassonografia
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