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Natural phenolic compounds have antioxidant properties owing to their free radical-scavenging capability. The combined effect of a mixture of phenolic compounds has been studied; however, the detailed investigation for finding a correlation between single phenolic molecules and antioxidant activity has not been explored. Herein, we revealed that the number of phenolic hydroxyl groups in phenolics played a central role in their antioxidant capacity. Based on the finding, tannic acid showed the most effective antioxidant potential, e.g., 76% in tannic acid versus 22% in vitamin C as a standard antioxidant component. Because cancer progression is closely related to oxidative processes at the cellular level, we further applied the surface treatment of tannic acid drug-delivery nanocarriers. Tannic acid-loaded nanocarriers reduced reactive oxygen species of cancer cells as much as 41% of vehicle treatment and remodeled cytoskeletal network. By a gelatin degradation study, TA-loaded nanocarrier-treated cells induced 44.6% reduction of degraded area than vehicle-treated cells, implying a potential of blocking invasiveness of cancer cells.
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Antioxidantes , Neoplasias , Antioxidantes/farmacologia , Fenóis/farmacologia , Oxirredução , Taninos/farmacologia , Espécies Reativas de OxigênioRESUMO
The understanding of the endocytosis process of internalized nanomedicines through membrane biomarker is essential for the development of molecular-specific nanomedicines. In various recent reports, the metalloproteases have been identified as important markers during the metastasis of cancer cells. In particular, MT1-MMP has provoked concern due to its protease activity in the degradation of the extracellular matrix adjacent to tumors. Thus, in the current work, we have applied fluorescent Au nanoclusters which present strong resistance to chemical quenching to the investigation of MT1-MMP-mediated endocytosis. We synthesized protein-based Au nanocluster (PAuNC) and MT1-MMP-specific peptide was conjugated with PAuNC (pPAuNC) for monitoring protease-mediated endocytosis. The fluorescence capacity of pPAuNC was investigated and MT1-MMP-mediated intracellular uptake of pPAuNC was subsequently confirmed by a co-localization analysis using confocal microscopy and molecular competition test. Furthermore, we confirmed a change in the intracellular lipophilic network after an endocytosis event of pPAuNC. The identical lipophilic network change did not occur with the endocytosis of bare PAuNC. By classification of the branched network between the lipophilic organelles at the nanoscale, the image-based analysis of cell organelle networking allowed the evaluation of nanoparticle internalization and impaired cellular components after intracellular accumulation at a single-cell level. Our analyses suggest a methodology to achieve a better understanding of the mechanism by which nanoparticles enter cells.
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Redox-active metal ions are pivotal for rapid metabolism, proliferation, and aggression across cancer types, and this presents metal chelation as an attractive cancer cell-targeting strategy. Here, we identify a metal chelator, KS10076, as a potent anti-cancer drug candidate. A metal-bound KS10076 complex with redox potential for generating hydrogen peroxide and superoxide anions induces intracellular reactive oxygen species (ROS). The elevation of ROS by KS10076 promotes the destabilization of signal transducer and activator of transcription 3, removes aldehyde dehydrogenase isoform 1-positive cancer stem cells, and subsequently induces autophagic cell death. Bioinformatic analysis of KS10076 susceptibility in pan-cancer cells shows that KS10076 potentially targets cancer cells with increased mitochondrial function. Furthermore, patient-derived organoid models demonstrate that KS10076 efficiently represses cancer cells with active KRAS, and fluorouracil resistance, which suggests clinical advantages.
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Morte Celular Autofágica , Fator de Transcrição STAT3 , Família Aldeído Desidrogenase 1 , Apoptose , Linhagem Celular Tumoral , Quelantes , Humanos , Células-Tronco Neoplásicas/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Superóxidos/metabolismoRESUMO
Bone morphogenetic protein-7 (BMP-7) antagonizes transforming growth factor-ß (TGF-ß), which is critically involved in liver fibrogenesis. Here, we designed a micelle formulation consisting of a protein transduction domain (PTD) fused BMP-7 polypeptide (mPTD-BMP-7) to enhance endocytic delivery, and investigated its ability to ameliorate liver fibrosis. The mPTD-BMP-7 formulation was efficiently delivered into cells via endocytosis, where it inhibited TGF-ß mediated epithelial-mesenchymal transition. After successfully demonstrating delivery of fluorescently labeled mPTD-BMP-7 into the murine liver in vivo, we tested the mPTD-BMP-7 formulation in a murine liver fibrosis model, developed by repeated intraperitoneal injection of hepatotoxic carbon tetrachloride, twice weekly from 4 to 16 weeks. mPTD-BMP-7 effects were tested by injecting the mPTD-BMP-7 formulation (or vehicle control) into the lateral tail at a dose of 50 (n=8) or 500 µg/kg (n=10), also twice per week from 4 to 16 weeks. Vehicle-treated control mice developed fibrous septa surrounding the liver parenchyma and marked portal-to-portal bridging with occasional nodules, whereas mice treated with mPTD-BMP-7 showed only fibrous expansion of some portal areas, with or without short fibrous septa. Using the Ishak scoring system, we found that the fibrotic burden was significantly lower in mPTD-BMP-7 treated mice than in control mice (all P<0.001). Treatment with mPTD-BMP-7 protected tight junctions between hepatocytes and reduced extracellular matrix protein levels. It also significantly decreased mRNA levels of collagen 1A, smooth muscle α-actin, and connective tissue growth factor compared with that in control mice (all P<0.001). Collectively, out results indicate that mPTD-BMP-7, a prodrug formulation of BMP-7, ameliorates liver fibrosis by suppressing the TGF-ß signaling pathway in a murine liver fibrosis model.
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PURPOSE: The positron emission tomography (PET)-magnetic resonance (MR) system is a newly emerging technique that yields hybrid images with high-resolution anatomical and metabolic information. With PET-MR imaging, a definitive diagnosis of breast abnormalities will be possible with high spatial accuracy and images will be acquired for the optimal fusion of anatomic locations. Therefore, we propose a PET-compatible two-channel breast MR coil with minimal disturbance to image acquisition which can be used for simultaneous PET-MR imaging in patients with breast cancer. MATERIALS AND METHODS: For coil design and construction, the conductor loops of the Helmholtz coil were tuned, matched, and subdivided with nonmagnetic components. Element values were optimized with an electromagnetic field simulation. Images were acquired on a GE 600 PET-computed tomography (CT) and GE 3.0 T MR system. For this study, we used the T1-weighted image (volunteer; repetition time (TR), 694 ms; echo time (TE), 9.6 ms) and T2-weighted image (phantom; TR, 8742 ms; TE, 104 ms) with the fast spin-echo sequence. RESULTS: The results of measuring image factors with the proposed radiofrequency (RF) coil and standard conventional RF coil were as follows: signal-to-noise ratio (breast; 207.7 vs. 175.2), percent image uniformity (phantom; 89.22%-91.27% vs. 94.63%-94.77%), and Hounsfield units (phantom; -4.51 vs. 2.38). CONCLUSIONS: Our study focused on the feasibility of proposed two-channel Helmholtz loops (by minimizing metallic components and soldering) for PET-MR imaging and found the comparable image quality to the standard conventional coil. We believe our work will help significantly to improve image quality with the development of a less metallic breast MR coil.
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Artefatos , Mama , Mama/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Imagens de Fantasmas , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND/AIM: We previously identified KS40008 (4-(3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzene-1,2-diol), a novel inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase family (DYRK) 1A/B, which exhibited high enzymatic activity and cell proliferation-inhibitory effects in colorectal cancer (CRC) cell lines. In the present study, we aimed to elucidate the antitumor mechanisms of KS40008. MATERIALS AND METHODS: To assess the cytotoxicity of KS40008, we utilized a human cell line and organoid model and performed a CCK-8 assay and real-time cell analysis. Mitochondrial function was determined through mitochondrial staining, mito-stress test, and glycolysis test. In addition, we investigated the mechanisms of cancer cell death induced by KS40008 through immunoblotting, real-time quantitative polymerase chain reaction, reactive oxygen species staining, and immunofluorescence staining. RESULTS: KS40008 exhibited significant cytotoxicity in CRC and non-CRC cell lines, and organoid models compared to 5-fluorouracil, a conventional chemotherapeutic drug. Moreover, KS40008-induced inhibition of DYRK1A/B led to mitochondrial dysfunction and endoplasmic reticulum stress, promoting autophagic cancer cell death. CONCLUSION: KS40008 exerts antitumor activity through the inhibition of DYRK1A/B. Here, we demonstrated a mechanism by which KS40008 affects endoplasmic reticulum stress-mediated autophagy through the induction of mitochondrial stress, leading to cytotoxicity in CRC.
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Morte Celular Autofágica/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reprogramação Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Fluoruracila/farmacologia , Glicólise/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases DyrkRESUMO
PURPOSE: Adjuvant radiotherapy (RT) has been performed to reduce locoregional failure (LRF) following radical cystectomy for locally advanced bladder cancer; however, its efficacy has not been well established. We analyzed the locoregional recurrence patterns of post-radical cystectomy to identify patients who could benefit from adjuvant RT and determine the optimal target volume. MATERIALS AND METHODS: We retrospectively reviewed 160 patients with stage ≥ pT3 bladder cancer who were treated with radical cystectomy between January 2006 and December 2015. The impact of pathologic findings, including the stage, lympho-vascular invasion, perineural invasion, margin status, nodal involvement, and the number of nodes removed on failure patterns, was assessed. RESULTS: Median follow-up period was 27.7 months. LRF was observed in 55 patients (34.3%), 12 of whom presented with synchronous local and regional failures as the first failure. The most common failure pattern was distant metastasis (40%). Among LRFs, the most common recurrence site was the cystectomy bed (15.6%). Patients with positive resection margins had a significantly higher recurrence rate compared to those without (28% vs. 10%, p=0.004). The pelvic nodal recurrence rate was < 5% in pN0 patients; the rate of recurrence in the external and common iliac nodes was 12.5% in pN+ patients. The rate of recurrence in the common iliac nodes was significantly higher in pN2-3 patients than in pN0-1 patients (15.2% vs. 4.4%, p=0.04). CONCLUSION: Pelvic RT could be beneficial especially for those with positive resection margins or nodal involvement after radical cystectomy. Radiation fields should be optimized based on the patient-specific risk factors.
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Cistectomia , Neoplasias da Bexiga Urinária , Humanos , Recidiva Local de Neoplasia/epidemiologia , Radio-Oncologistas , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/radioterapia , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
Sentinel lymph node (SLN) biopsy has gained attention as a method of minimizing the extent of neck dissection with a similar survival rate as elective neck dissection in oral cancer. Indocyanine green (ICG) imaging is widely used in the field of surgical oncology. Real-time ICG-guided SLN imaging has been widely used in minimally invasive surgeries for various types of cancers. Here, we provide an overview of conventional SLN biopsy and ICG-guided SLN mapping techniques for oral cancer. Although ICG has many strengths, it still has limitations regarding its potential use as an ideal compound for SLN mapping. The development of novel fluorophores and imaging technology is needed for accurate identification of SLNs, which will allow precision surgery that would reduce morbidities and increase patient survival.
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The purpose of this study was to evaluate the diagnostic performance of magnetic resonance (MR) radiomics-based machine learning algorithms in differentiating squamous cell carcinoma (SCC) from lymphoma in the oropharynx. MR images from 87 patients with oropharyngeal SCC (n=68) and lymphoma (n=19) were reviewed retrospectively. Tumors were semi-automatically segmented on contrast-enhanced T1-weighted images registered to T2-weighted images, and radiomic features (n=202) were extracted from contrast-enhanced T1- and T2-weighted images. The radiomics classifier was built using elastic-net regularized generalized linear model analyses with nested five-fold cross-validation. The diagnostic abilities of the radiomics classifier and visual assessment by two head and neck radiologists were evaluated using receiver operating characteristic (ROC) analyses for distinguishing SCC from lymphoma. Nineteen radiomics features were selected at least twice during the five-fold cross-validation. The mean area under the ROC curve (AUC) of the radiomics classifier was 0.750 [95% confidence interval (CI), 0.613-0.887], with a sensitivity of 84.2%, specificity of 60.3%, and an accuracy of 65.5%. Two human readers yielded AUCs of 0.613 (95% CI, 0.467-0.759) and 0.663 (95% CI, 0.531-0.795), respectively. The radiomics-based machine learning model can be useful for differentiating SCC from lymphoma of the oropharynx.
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Carcinoma de Células Escamosas/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Neoplasias Orofaríngeas/diagnóstico por imagem , Orofaringe/diagnóstico por imagem , Algoritmos , Biópsia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Aumento da Imagem/métodos , Linfoma/patologia , Aprendizado de Máquina , Neoplasias Orofaríngeas/patologia , Orofaringe/patologia , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
A gold nanoparticle-based localized surface plasmon resonance substrate has been developed as nano-sensors for various bio-applications. However, reproducible and robust sensing substrates anchored gold nanoparticles has not yet been explored. In this study, dopamine-coated gold nanorods (DGNRs) were prepared and immobilized onto the micro-grooving PDMS substrates (mgPDMS). Subsequently, HER2-specific aptamers were conjugated with DGNR/mgPDMS for ECD-HER2 detection. By screening of the optimal concentration of DGNR and aptamers, the effective HER2-specific aptasensor was built up. In particular, the real-time binding assay for the evaluation of limit-of-detection (<5 ng ml-1) was conducted. Furthermore, the binding kinetics for ECD-HER2 was investigated under the biological fluid using a rat serum. Our HER2-specific aptasensor demonstrated the effective sensitivity and selectivity for ECD-HER2.
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Aptâmeros de Nucleotídeos/química , Dopamina/química , Receptor ErbB-2/análise , Animais , Técnicas Biossensoriais , Ouro , Limite de Detecção , Masculino , Nanopartículas Metálicas , Ratos , Receptor ErbB-2/sangue , Ressonância de Plasmônio de SuperfícieRESUMO
Polydiacetylene-based nanoparticles have been developed as nanocarriers for various bio-applications. However, how nanocarriers enter the cell environment and affect cell viability has not yet been considerably explored. In this study, polydiacetylene-based nanoliposomes (nanosomes) were electrostatically complexed with rhodamine fluorophores. Based on real-time cell imaging and cell viability assessment, the most highly polymerized nanosomes were found to be less toxic to cells. Moreover, it was revealed that the rhodamine/polydiacetylene nanosome complex dissociates at cell environment, the polydiacetylene nanosome penetrates into cells, as suggested by the fluorescence observed in confocal microscopy images.
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Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Nanopartículas/administração & dosagem , Polímero Poliacetilênico/administração & dosagem , Linhagem Celular Tumoral , Humanos , Lipossomos/administração & dosagem , Lipossomos/química , Nanopartículas/química , Polímero Poliacetilênico/químicaRESUMO
Epidermal growth factor receptor (EGFR) overexpression is common in head and neck squamous cell carcinoma. Targeted therapy specifically directed towards EGFR has been an area of keen interest in head and neck cancer research, as EGFR is potentially an integration point for convergent signaling. Despite the latest advancements in cancer diagnostics and therapeutics against EGFR, the survival rates of patients with advanced head and neck cancer remain disappointing due to anti-EGFR resistance. This review article will discuss recent multilateral efforts to discover and validate actionable strategies that involve signaling pathways in heterogenous head and neck cancer and to overcome anti-EGFR resistance in the era of precision medicine. Particularly, this review will discuss in detail the issue of cancer metabolism, which has recently emerged as a novel mechanism by which head and neck cancer may be successfully controlled according to different perspectives.
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Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de SinaisRESUMO
Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has been a longstanding challenge for head and neck oncologists, and current treatments still have limited efficacy. ERK is aberrantly overexpressed and activated in HNSCC. Herein, we aimed to investigate the cause of the limited therapeutic effect of selumetinib, a selective inhibitor of MEK in HNSCC, as MEK/ERK reactivation inevitably occurs. We assessed the effects of combining selumetinib with fibroblast growth factor receptor 3 (FGFR3) inhibitor (PD173074) on tumor growth. Selumetinib transiently inhibited MAPK signaling and reactivated ERK signaling in HNSCC cells. Rebound in the ERK and Akt pathways in HNSCC cells was accompanied by increased FGFR3 signaling after selumetinib treatment. Feedback activation of FGFR3 was a result of autocrine secretion of the FGF2 ligand. The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib. These results provided rational therapeutic strategies for clinical studies of this subtype of patients that show a poor prognosis with selumetinib. Our data provide a rationale for combining a MEK inhibitor with inhibitors of feedback activation of FGFR3 signaling in HNSCC cells. ERK rebound as a result of the upregulation of FGFR3 and the ligand FGF2 diminished the antitumor effects of selumetinib, which was overcome by combination treatment with the FGFR3 inhibitor.
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Benzimidazóis/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Pirimidinas/administração & dosagem , Receptor ErbB-3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Pirimidinas/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Biophysical properties are intimately connected to metastatic functions and aggressiveness in cancers. Especially, cellular stiffness is regarded as a biomarker for the understanding of metastatic potential and drug sensitivity. Here, protease-mediated changes of cortical stiffness are identified due to the deformation of cytoskeleton alignment at a cortex. For the past few decades, membrane type 1-matrix metalloproteinase (MT1-MMP) has been well known as a kernel protease enriched in podosomes during metastasis for extracellular matrix degradation. However, the biophysical significance of MT1-MMP expressing cancer cells is still unknown. Therefore, the nanomechanics of cancer cells is analyzed by a nanoindentation using a microsphere-attached cantilever of atomic force microscopy (AFM). In conclusion, the results suggest that MT1-MMP has contributed as a key regulator in cytoskeletal deformation related with cancer metastasis. Particularly, the AFM-based nanoindentation system for the monitoring of cortical nanomechanics will be crucial to understand molecular networks in cancers.
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Metaloproteinase 14 da Matriz/química , Microesferas , Citoesqueleto/química , Microscopia de Força AtômicaRESUMO
Gold nanorods (GNRs) are of great interest in cancer therapy given their ability to ablate tumor cells using deep tissue-penetrating near-infrared light. GNRs coated with tumor-specific moieties have the potential to target tumor tissue to minimize damage to normal tissue. However, perfect targeting is difficult to achieve given that nanoparticles could be broadly dispersed inside the body. Moreover, interaction between targeting groups and biological molecules could lower targeting abilities, resulting in off-target accumulation which might produce nanotoxicity. Here we introduce GNR-encapsulated microcubes (GNR@MCs) that can be utilized as implantable photothermal agents. GNR@MCs are created by encapsulating GNRs in polymeric networks via stop flow lithography (SFL), a one-phase synthesis technique which allows for creation of surfactant-free, uniform particles, and injection of GNR@MCs into the body after a simple rinse step. GNRs are highly packed and firmly encapsulated inside MCs, and entrapped GNRs exhibit optical properties comparable to that of unbound GNRs and photothermal efficiency (58%) in line with that of nano-sized agents (51-95%). Photothermal ablation in murine models is achieved using GNR@MCs stably implanted into the tumor tissue, which suggests that GNR@MCs can be a safe and effective platform for cancer therapy.
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Ouro/farmacologia , Fototerapia/métodos , Animais , Linhagem Celular Tumoral , Camundongos , NanotubosRESUMO
The aim of this study was the development of a human epidermal growth factor receptor 2 (HER2)-targetable contrast agent for magnetic resonance imaging (MRI) with a high magnetic sensitivity. An anti-HER2 aptamer-modified magnetic nanosensitizer (AptHER2-MNS) was prepared by conjugation with 5'-thiol-modified aptamers and maleimidylated magnetic nanocrystals (MNCs). The physicochemical characteristics and targeting ability of AptHER2-MNS were confirmed, and the binding affinity (Kd) onto HER2 protein of AptHER2-MNS was 0.57 ± 0.26 nM. In vivo MRI contrast enhancement ability was also verified at HER2+ cancer cell (NIH3T6.7)-xenograft mouse models (n = 3) at 3T clinical MRI instrument. The control experiment was carried out using non-labeled MNCs. The results indicated that up to 150% contrast enhancement was achieved at the tumor region in the T2-weighted MR images after the injection of the AptHER2-MNS agent in mice that received the NIH3T6.7 cells.
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Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C and BCPAP were selected and treated with BRAF inhibitor, PLX4032 and its effect on EMT were examined and compared. Further investigation was carried out in orthotopic xenograft mouse models. Unlike BCPAP cells, the BRAF inhibitor resistant 8505C cells showed increased expressions of EMT related markers such as vimentin, ß-catenin, and CD44. The combinatorial treatment of PLX4032 and PHA665752, a c-Met inhibitor reversed EMT. Similar results were confirmed in vivo. c-Met-mediated reactivation of the PI3K/AKT pathway contributes to the drug resistance to PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer cells and further promotes tumor cell migration and invasion by upregulated EMT mechanism. Dual inhibition of BRAF and c-Met leads to reversal of EMT, suggesting a maximal therapeutic response.
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Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Humanos , Indóis/farmacologia , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Vemurafenib , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Real-time screening of cellular response on the drugs could provide valuable insights for the early detection of therapeutic efficiency and the evaluation of disease progression. Cancer cells have the ability to vary widely in response to stress in a manner to adjust the signaling pathway to promote the survival or having a resistance to stimulation. Cell-based label-free technologies using electronic impedance sensor have strategies for constructing the signature profiles of each cells. To achieve exquisite sensitivity to substantially change of live-cell response have an important role that predict the potential of therapeutic effects. In this study, we use an impedance-based real-time cell analysis system to investigate dynamic phenotypes of cells described as a cellular index value. We show that gastric cancer cells generated characteristic kinetic patterns that corresponded to the treatment order of therapeutics. The kinetic feature of the cells offers insightful information that cannot be acquired from a conventional single end-point assay. Furthermore, we employ a 'sequential treatment strategy' to increase cytotoxic effects with minimizing the use of chemotherapeutics. Specifically, treatment of paclitaxel (PTX) after down-regulating Akt gene expression using RNAi reduces the cell proliferation and increases apoptosis. We propose that the sequential treatment may exhibit more effective approach rather than traditional combination therapy. Moreover, the dynamic monitoring of cell-drug interaction enables us to obtain a better understanding of the temporal effects in vitro.
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Proliferação de Células/efeitos dos fármacos , Paclitaxel/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/biossíntese , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
Novel diagnostic techniques have been developed in many research area using targetable contrast agents with magnetic resonance imaging (MRI) for cancer diagnosis. For cancer diagnosis, the use of MRI with biocompatible targeting moieties and manganese ferrite nanoparticles (MFNPs) is preferred. Thus, we synthesized MFNPs using a thermal decomposition method which enables sensitive T2 or T2 Turbo Spin Echo (TSE) MRI and coated them with hyaluronic acid (HA). The high targeting ability of HA-MFNPs was observed at MKN-45 cells (gastric cancer cell line) which high-expressing CD44 in contrast with MKN-28 cells which low-expressing CD44. We also prepared the gastric cancer mice model using MKN-45 cells which has the stem-like property was implanted into BALB/c nude mice. And then HA-MFNPs of the T2 contrast enhancement effects and targeting ability were investigated by in vivo MR imaging. As a result of these studies, we conclude that HA coated MFNPs can be effectively used as a novel probes for visualizing gastric cancer stem cells.
Assuntos
Meios de Contraste , Compostos Férricos , Receptores de Hialuronatos/biossíntese , Compostos de Manganês , Imagem Molecular/métodos , Nanopartículas/química , Proteínas de Neoplasias/biossíntese , Neoplasias Experimentais , Neoplasias Gástricas , Animais , Meios de Contraste/química , Meios de Contraste/farmacologia , Feminino , Compostos Férricos/química , Compostos Férricos/farmacologia , Imageamento por Ressonância Magnética , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Radiografia , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/metabolismoRESUMO
Near-infrared (NIR) fluorophores attract increasing attention as a molecular marker (or probe) for in vivo and in vitro biological fluorescence imaging. Three types of new NIR fluorescent conjugated oligoelectrolytes (COEs: Q-FlTBTTFl, Q-FlBBTFl, and Q-FlTBBTTFl) are synthesized with quaternized ammonium ionic groups in their side-chains for water solubility. The emission wavelength is modulated in the range 600-1300 nm, by adjusting the intramolecular charge transfer in the molecular backbone based on the electron-rich fluorene (and/or thiophene) and electron-deficient benzo[2,1,3]thiadiazole (or benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole) moieties. The COEs show a remarkably larger Stokes shift (147-276 nm) compared to commercial rhodamine and cyanine dyes in water, avoiding self-quenching and interference from the excitation backscattered light. The photoluminescence (PL) quantum efficiency is improved substantially by up to 27.8% in water by fabricating a vesicular complex, COE/v, with a block ionomer, poly[(ethylene oxide)-block-(sodium 2-acrylamido-2-methyl-1-propanesulfonate)]. In vitro cellular uptake images with the COEs are obtained with good biocompatibility by confocal single-photon and two-photon microscopy. The ex vivo and in vivo images of a mouse xenograft model treated with the Q-FlBBTFl/v exhibit a substantially stronger fluorescence signal at the tumor site than at the other organs, highlighting the potential of the COE/v as an NIR fluorescent imaging agent for the diagnosis of cancer.