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1.
Am J Physiol Cell Physiol ; 325(3): C708-C720, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37575061

RESUMO

Breast cancer is the leading cause of cancer deaths for women worldwide. Endocrine therapies represent the cornerstone for hormone-dependent breast cancer treatment. However, in many cases, endocrine resistance is induced with poor prognosis for patients. In the current study, we have developed MCF-7 cell lines resistant to fulvestrant (MCF-7Fulv) and tamoxifen (MCF-7Tam) aiming at investigating mechanisms underlying resistance. Both resistant cell lines exerted lower proliferation capacity in two-dimensional (2-D) cultures but retain estrogen receptor α (ERα) expression and proliferate independent of the presence of estrogens. The established cell lines tend to be more aggressive exhibiting advanced capacity to form colonies, increased expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and heterodimerization of ERBB family receptors and activation of EGFR downstream pathways like MEK/ERK1/2 and PI3K/AKT. Tyrosine kinase inhibitors tested against resistant MCF-7Fulv and MCF-7Tam cells showed moderate efficacy to inhibit cell proliferation, except for lapatinib, which concomitantly inhibits both EGFR and HER2 receptors and strongly reduced cell proliferation. Furthermore, increased autophagy was observed in resistant MCF-7Fulv and MCF-7Tam cells as shown by the presence of autophagosomes and increased Beclin-1 levels. The increased autophagy in resistant cells is not associated with increased apoptosis, suggesting a cytoprotective role for autophagy that may favor cells' survival and aggressiveness. Thus, by exploiting those underlying mechanisms, new targets could be established to overcome endocrine resistance.NEW & NOTEWORTHY The development of resistance to hormone therapy caused by both fulvestrant and tamoxifen promotes autophagy with concomitant apoptosis evasion, rendering cells capable of surviving and growing. The fact that resistance also triggers ERBB family signaling pathways, which are poorly inhibited by tyrosine kinase inhibitors might attribute to cells' aggressiveness. It is obvious that the development of endocrine therapy resistance involves a complex interplay between deregulated ERBB signaling and autophagy that may be considered in clinical practice.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Fulvestranto/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Proliferação de Células , Células MCF-7 , Autofagia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo
2.
Molecules ; 22(7)2017 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-28696397

RESUMO

In this study, we assessed the therapeutic potential of propolis from Poland and performed chemical analysis by GC-MS, as well as determined its botanical origin. Chemical constituents typical for bud exudates of Populusnigra (section Aigeiros) were determined, however, glycerol esters of phenolic acids, as well as unusually high amounts of p-coumaric and ferulic acid and their benzyl esters, were also detected. These constituents are characteristic for buds of Populustremula (section Leuce). We also evaluated the antiproliferative effect of propolis extracts against nine human cancer cell lines. Additionally, promising antibacterial activity of the dichloromethane extract (Minimal Inhibitory Concentration MIC values of 0.95-1.24 mg/mL), as well as a moderate antifungal activity (MIC values of 1.25-1.40 mg/mL), was noticed. Propolis from Poland appeared as a rich source of antibacterial and antiproliferative compounds and this confirmed that it is a valuable natural product with the potential to improve human health.


Assuntos
Própole/química , Antibacterianos/química , Antifúngicos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Ácidos Cumáricos/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hidroxibenzoatos/química , Polônia
3.
Hum Genomics ; 9: 12, 2015 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-26092435

RESUMO

Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance.


Assuntos
Predisposição Genética para Doença , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Proteína BRCA1/genética , Proteínas de Ligação a DNA/genética , Humanos , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas de Neoplasias/genética , Neoplasias/patologia , Linhagem , Polimorfismo de Nucleotídeo Único
4.
Cancer Invest ; 33(8): 387-97, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26115385

RESUMO

This study aims to address the role of focal adhesion proteins α- and ß-parvin in human colorectal carcinoma (CRC). Expression of α- and ß-parvin was examined by immunohistochemistry and real-time RT-PCR in a series of human CRC. Parvins were overexpressed in CRC and their expression correlated significantly with tumor invasion, lymph node metastasis, and disease stage. A significant positive correlation of parvins protein expression with overexpression of integrin-linked kinase, p-AKT, and nuclear ß-catenin, as well as with downregulation of E-cadherin was also observed. In conclusion, overexpression of α- and ß-parvin seems to be implicated in human colorectal cancer progression.


Assuntos
Actinina/metabolismo , Neoplasias Colorretais/patologia , Proteínas dos Microfilamentos/metabolismo , Actinina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Caderinas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/genética , Masculino , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Valores de Referência , Adulto Jovem , beta Catenina/metabolismo
5.
J Biomed Sci ; 22: 98, 2015 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-26497899

RESUMO

BACKGROUND: Notch may behave as an oncogene or a tumor suppressor gene in lung cancer cells. Notch receptor undergoes cleavage by enzymes, including γ-secretase, generating the active Notch intracellular domain (NICD). The aim of the present study was to investigate the effect of DAPT, a γ-secretase inhibitor, in non-small cell lung cancer (NSCLC) cells, as well as the impact of epidermal growth factor (EGF) that is over-expressed by NSCLC cells, on Notch signaling. H23, A549, H661 and HCC827 human NSCLC cell lines were used, expressing various NICD and EGF receptor (EGFR) protein levels. RESULTS: DAPT decreased the number of H661 cells in a concentration-dependent manner, while it had a small effect on H23 and A549 cells and no effect on HCC827 cells that carry mutated EGFR. Notch inhibition did not affect the stimulatory effect of EGF on cell proliferation, while EGF prevented DAPT-induced NICD decrease in H23 and H661 cells. The type of cell death induced by DAPT seems to depend on the cell type. CONCLUSIONS: Our data indicate that inhibition of Notch cleavage may not affect cell number in the presence of EGFR mutations and that EGFR may affect Notch signalling suggesting that a dual inhibition of these pathways might be promising in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Mutação , Receptores Notch/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores Notch/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/genética
6.
Hum Genomics ; 7: 14, 2013 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-23738773

RESUMO

A large number of common disorders, including cancer, have complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. A literature search revealed that even among several meta-analyses, there were ambiguous results and conclusions. In the current study, we conducted a thorough meta-analysis gathering the published meta-analysis studies previously reported to correlate any random effect or predictive value of genome variations in certain genes for various types of cancer. The overall analysis was initially aimed to result in associations (1) among genes which when mutated lead to different types of cancer (e.g. common metabolic pathways) and (2) between groups of genes and types of cancer. We have meta-analysed 150 meta-analysis articles which included 4,474 studies, 2,452,510 cases and 3,091,626 controls (5,544,136 individuals in total) including various racial groups and other population groups (native Americans, Latinos, Aborigines, etc.). Our results were not only consistent with previously published literature but also depicted novel correlations of genes with new cancer types. Our analysis revealed a total of 17 gene-disease pairs that are affected and generated gene/disease clusters, many of which proved to be independent of the criteria used, which suggests that these clusters are biologically meaningful.


Assuntos
Biomarcadores Tumorais/genética , Detecção Precoce de Câncer , Genoma Humano/genética , Metanálise como Assunto , Neoplasias/diagnóstico , Neoplasias/genética , Epistasia Genética , Genes Neoplásicos/genética , Humanos , Neoplasias/classificação , Polimorfismo de Nucleotídeo Único/genética
7.
Pharm Biol ; 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-24192333

RESUMO

Abstract Context: Estrogens in non-small-cell lung cancer (NSCLC) are important, and their interaction with epidermal growth factor receptor (EGFR) might be crucial. Objective: This study investigates the effect of exemestane, an aromatase inhibitor, and erlotinib, an EGFR inhibitor, on human NSCLC cell lines; H23, H358 and A549. Materials and methods: A cell proliferation assay was used for measuring cell number, apoptosis assay for detecting apoptosis and necrosis and immunoblotting for beclin-1 and Bcl-2 proteins detection. An immunofluorescence assay was used for EGFR localization. A migration assay and zymography were used for cell motility and metalloproteinases (MMPs) expression, respectively. Results: Exemestane, erlotinib or their combination decreased cell proliferation and increased apoptosis. Exemestane's half maximal inhibitory concentration (IC50) was 50 µM for H23 and H358 cells and 20 µM for A549. The IC50 of erlotinib was 25 µM for all cell lines. Apoptosis increase induced by exemestane was 58.0 (H23), 186.3 (H358) and 34.7% (A549) and by erlotinib was 16.7 (H23), 65.3 (H358) and 66.3% (A549). A synergy effect was observed only in H23 cells. Noteworthy, the combination of exemestane and erlotinib decreased beclin-1 protein levels (32.3 ± 19.2%), an indicator of autophagy, in H23 cells. The combination of exemestane and erlotinib partially reversed the EGFR translocation to mitochondria and decreased MMP levels and migration. Discussion and conclusions: The benefit from a dual targeting of aromatase and EGFR seems to be regulated by NSCLC cell content. The diverse responses of cells to agents might be influenced by the dominance of certain molecular pathways.

8.
Dalton Trans ; 52(10): 2937-2941, 2023 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-36825841

RESUMO

A synthetically controllable two-step spin transition was observed in iron(II) spin crossover nanoparticles of the dehydrated one-dimensional coordination polymer [Fe(NH2trz)3]Br2 (NH2trz = 4-amino-1,2,4-triazole) using the reverse micellar method. The change from two-step to one-step hysteretic characteristics succeeded by changing the reaction time.

9.
Cancer Invest ; 30(2): 172-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22149178

RESUMO

In the present study we assessed the expression and distribution of endoribonuclease Dicer in soft tissue tumors and correlated its cellular levels with clinicopathological parameters, including clinical outcome. Dicer was expressed in the tested cell line as well as in the majority of the sarcomas examined. Staining intensity was significantly higher in sarcomas compared with benign neoplasms and in high-grade compared with low-grade tumors. Elevated Dicer immunoreactivity was strongly associated with poor outcome and Dicer cellular levels were an independent negative prognostic factor.


Assuntos
RNA Helicases DEAD-box/metabolismo , Leiomiossarcoma/enzimologia , Ribonuclease III/metabolismo , Neoplasias de Tecidos Moles/enzimologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Leiomiossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Tecidos Moles/patologia , Adulto Jovem
10.
Front Oncol ; 12: 811508, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052248

RESUMO

The onset and progression of cancer are strongly associated with the dissipation of adhesion forces between cancer cells, thus facilitating their incessant attachment and detachment from the extracellular matrix (ECM) to move toward metastasis. During this process, cancer cells undergo mechanical stresses and respond to these stresses with membrane deformation while inducing protrusions to invade the surrounding tissues. Cellular response to mechanical forces is inherently related to the reorganization of the cytoskeleton, the dissipation of cell-cell junctions, and the adhesion to the surrounding ECM. Moreover, the role of focal adhesion proteins, and particularly the role of vinculin in cell attachment and detachment during migration, is critical, indicating the tight cell-ECM junctions, which favor or inhibit the metastatic cascade. The biomechanical analysis of these sequences of events may elucidate the tumor progression and the potential of cancer cells for migration and metastasis. In this work, we focused on the evaluation of the spreading rate and the estimation of the adhesion strength between breast cancer cells and ECM prior to and post-treatment with anti-tumor agents. Specifically, different tamoxifen concentrations were used for ER+ breast cancer cells, while even concentrations of trastuzumab and pertuzumab were used for HER2+ cells. Analysis of cell stiffness indicated an increased elastic Young's modulus post-treatment in both MCF-7 and SKBR-3 cells. The results showed that the post-treatment spreading rate was significantly decreased in both types of breast cancer, suggesting a lower metastatic potential. Additionally, treated cells required greater adhesion forces to detach from the ECM, thus preventing detachment events of cancer cells from the ECM, and therefore, the probability of cell motility, migration, and metastasis was confined. Furthermore, post-detachment and post-treatment vinculin levels were increased, indicating tighter cell-ECM junctions, hence limiting the probability of cell detachment and, therefore, cell motility and migration.

11.
Invest New Drugs ; 28(5): 554-60, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19603143

RESUMO

AIM: We sought to assess the effect of sunitinib and lapatinib applied either alone or in combination, on U87 and M059K glioma cells. METHODS: Both cell lines were cultured as recommended by the manufacturer. Sunitinib and lapatinib were applied, either separately or in combination, in the cultured cells after cell attachment at doses of 10 nM, 100 nM, 1 microM and 10 microM. To determine whether the agents affect the proliferation of glioma cells, the 3-[4,5-dimethylthiazol-2-yl]-2,5 dimethyltetrazolium bromide assay was used. Apoptosis was detected using annexin V/propidium iodide detection assay, migration assay was performed in 24-well microchemotaxis chambers. The release of MMPs into the culture medium of U87 and M059K cells was measured by zymography. RESULTS: Both agents, administered either alone or in combination, decreased cell proliferation in a dose-dependent manner 48 h after their application in both cell lines. The inhibition of their combination was statistically different than the inhibition of each agent alone. Apoptosis was increased and migration of U87 and M059K cells was inhibited either by each agent alone or their combination. MMPs levels remained unaffected by the application of both agents in U87 cells. However, MMP-9 and MMP-2 levels were decreased 48 h after treatment of M059K cells with sunitinib either alone or in combination with lapatinib. CONCLUSION: Sunitinib and/or lapatinib appear to exhibit significant effects on proliferation, apoptosis and migration of glioma cells. When applied alone, sunitinib appears to be a more potent inhibitor than lapatinib.


Assuntos
Glioma/tratamento farmacológico , Glioma/patologia , Indóis/farmacologia , Pirróis/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioma/enzimologia , Humanos , Indóis/uso terapêutico , Lapatinib , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pirróis/uso terapêutico , Quinazolinas/uso terapêutico , Sunitinibe
12.
Mol Cancer ; 8: 109, 2009 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-19930708

RESUMO

BACKGROUND: Recent evidence suggests that estrogen signaling may be involved in the pathogenesis of non-small cell lung cancer (NSCLC). Aromatase is an enzyme complex that catalyses the final step in estrogen synthesis and is present in several tissues, including the lung. In the current study we investigated the activity of the aromatase inhibitor exemestane in human NSCLC cell lines H23 and A549. RESULTS: Aromatase expression was detected in both cell lines. H23 cells showed lower protein and mRNA levels of aromatase, compared to A549 cells. Exemestane decreased cell proliferation and increased apoptosis in both cell lines, 48 h after its application, with A549 exhibiting higher sensitivity than H23 cells. Aromatase protein and mRNA levels were not affected by exemestane in A549 cells, whereas an increase in both protein and mRNA levels was observed in H23 cells, 48 h after exemestane application. Moreover, an increase in cAMP levels was found in both cell lines, 15 min after the administration of exemestane. In addition, we studied the effect of exemestane on epidermal growth factor receptor (EGFR) localization and activation. Exemestane increased EGFR activation 15 min after its application in H23 cells. Furthermore, we demonstrated a translocation of EGFR from cell membrane, 24 h after the addition of exemestane in H23 cells. No changes in EGFR activation or localization were observed in A549 cells. CONCLUSION: Our findings suggest an antiproliferative effect of exemestane on NSCLC cell lines. Exemestane may be more effective in cells with higher aromatase levels. Further studies are needed to assess the activity of exemestane in NSCLC.


Assuntos
Androstadienos/farmacologia , Neoplasias Pulmonares/patologia , Apoptose/efeitos dos fármacos , Aromatase/genética , Aromatase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Testosterona/farmacologia
13.
Oncology ; 77(1): 1-11, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19439998

RESUMO

Angiogenesis is considered to be a regulating factor of vascular development and growth for malignant gliomas, including glioblastoma multiforme (GBM) and anaplastic astrocytomas. The mechanism of angiogenesis is primarily mediated by hypoxia through chronic activation of the HIF pathway leading to the production of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. Alternatively, it can be triggered by genetic factors. The VEGF/VEGFR-2 is the predominant angiogenic signalling pathway in malignant gliomas. Currently, anti-angiogenic molecularly targeted therapies, including administration of monoclonal antibodies or tyrosine kinase inhibitors (TKIs), are being increasingly adopted for treating GBMs. This approach is based on the ability of anti-VEGFRs monoclonal antibodies to decrease vascular permeability and perfusion, whereas the use of TKIs is mainly based on their capacity to interfere with cell communication, receptor signaling and growth of tumours. Our aim is to review current knowledge on angiogenesis as a molecular pathogenetic mechanism of malignant gliomas and to critically look at and discuss antiangiogenic molecularly targeted therapies for these brain malignancies. We also highlight areas of future research to pursue.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Encefálicas/irrigação sanguínea , Glioma/irrigação sanguínea , Neovascularização Patológica/prevenção & controle , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos
14.
Lipids ; 54(10): 629-640, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31489677

RESUMO

Lipoprotein-associated phospholipase A2 (Lp-PLA2 ) is associated with increased risk of cardiovascular diseases (CVD) and type 2 diabetes mellitus. Lp-PLA2 activity is positively associated with male sex, Caucasian race, the presence of metabolic syndrome (MetS) and low-density lipoprotein (LDL)-cholesterol, but it is negatively associated with high-density lipoprotein (HDL)-cholesterol. Associations with other cardiometabolic risk factors, inflammation markers, and lifestyle factors are few or inconsistent. We investigated potential determinants of Lp-PLA2 activity among both nonmodifiable and modifiable CVD risk factors in a middle-aged Greek cohort without overt CVD. Two hundred eighty four subjects (159 men, 53 ± 9 years and 125 women 52 ± 9 years) participated in a cross-sectional study carried out during 2011-2012 in Athens, Attica. Cardiometabolic risk factors, inflammation markers, lifestyle factors, and Lp-PLA2 activity were evaluated with established methods. The American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria were used to define MetS. Lp-PLA2 activity was not associated with MetS, but was associated with MetS components, markers of liver function, and macronutrient intake. Increased total energy intake was associated with increased Lp-PLA2 activity (odds ratio, 95% confidence interval: 1.07, 1.01-1.14 and 1.10, 1.03-1.16 for the 4th and 3rd quartiles, respectively, compared to the 1st quartile) after adjustments for sex, pack-years of smoking, LDL-cholesterol, and statin treatment. Adiponectin tended to be inversely associated with Lp-PLA2 activity (0.91, 0.82-1.00, and 4th versus 1st quartile). Our results suggested that total energy intake and adiponectin levels are potential determinants of Lp-PLA2 activity.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Adiponectina/sangue , Ingestão de Energia , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Front Pharmacol ; 10: 384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31024324

RESUMO

Pharmacogenomics has been recognized as a fundamental tool in the era of personalized medicine with up to 266 drug labels, approved by major regulatory bodies, currently containing pharmacogenomics information. Next-generation sequencing analysis assumes a critical role in personalized medicine, providing a comprehensive profile of an individual's variome, particularly that of clinical relevance, comprising of pathogenic variants and pharmacogenomic biomarkers. Here, we propose a strategy to integrate next-generation sequencing into the current clinical pharmacogenomics workflow from deep resequencing to pharmacogenomics consultation, according to the existing guidelines and recommendations.

16.
Ann Biomed Eng ; 47(8): 1711-1724, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31098800

RESUMO

Studying human cancer from a biomechanical perspective may contribute to pathogenesis understanding which leads to the malignancy. In this study, biomechanics of suspended and adhered breast cancer cells were investigated via the micropipette aspiration method with special emphasis on comparing the cell stiffness and viscoelastic parameters of estrogen receptor positive, ER+, MCF-7 and human epidermal growth factor receptor 2 positive, HER2 +, SKBR-3 cancer cell lines prior to and post treatment with tamoxifen and trastuzumab, respectively. Alterations of mechanical parameters included significant increase in cell stiffness, especially after treatment with trastuzumab and changes in viscoelastic parameters, in both cancer cell lines post treatment. According to immunofluorescence analysis, the raised cell stiffness was corresponded to remodeling of F-actin, which peripherally located in tamoxifen treated and perinuclear accumulated in trastuzumab treated cancer cell cytoskeleton, implying a reduced potential for cell deformation and motility. Additionally, these results were in line with the study of single and collective cell migration through Boyden chamber and wound healing assays respectively, where the potential for migration was significantly decreased after treatment. Consequently, these findings lead to an increased interest in biomechanics of cancer progression after treatment with anti-tumor agents, importantly in understanding the effect of the alterations of mechanical properties upon the possibility for change in metastatic potential.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Tamoxifeno/farmacologia , Trastuzumab/farmacologia , Citoesqueleto de Actina/química , Actinas/química , Linhagem Celular Tumoral , Elasticidade , Humanos , Células MCF-7 , Viscosidade
17.
J Pharm Biomed Anal ; 164: 690-697, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30472587

RESUMO

Sunitinib is a multi-targeted tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor and is currently being investigated against other forms of malignant tumors. Recently great interest has emerged for the application of sunitinib to glioblastoma treatment. In order to have a method with broad applicability it will be of importance to have access to a method that could be applied both in human plasma and cell uptake studies. No method has been reported thus far for the estimation of sunitinib uptake in glioma cells. We therefore set out to develop a method that could be applied for quantifying sunitinib in human plasma and in cell uptake studies. The method was validated and accredited according to ISO 17025:2005 guideline in human plasma and successfully applied to cancer patient plasma. Also, the method was effectively recruited to establish a protocol for the evaluation of sunitinib accumulation into M095K glioma cells. This method could significantly contribute to developmental phases in repurposing this drug in different cancer types.


Assuntos
Antineoplásicos/análise , Carcinoma de Células Renais/sangue , Avaliação Pré-Clínica de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Neoplasias Renais/sangue , Inibidores de Proteínas Quinases/análise , Sunitinibe/análise , Administração Oral , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Reposicionamento de Medicamentos , Voluntários Saudáveis , Humanos , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Sunitinibe/sangue , Sunitinibe/uso terapêutico , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
18.
Expert Rev Pharmacoecon Outcomes Res ; 19(4): 491-501, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30417707

RESUMO

Background:Metastatic RCC (mRCC) treatment has been revolutionized with 11 approved targeted agents. We report patterns of practice, outcomes and pharmacoeconomic analyses after the introduction of targeted therapy. Patients and methods: CRISIS was a retrospective multicenter study of mRCCpatients who received targeted therapy . Results were related to the start of 1st-line therapy, with a cut off at 1 January 2011 in order to depict the impact of increased availability of effective options. Results: 164 patients, were included. 70.1% and 44.5% received 2nd and 3rd-line therapy, respectively. More patients were treated in 2nd-line after 1 January 2011. After a median follow-up of 55.1 months, median progression-free (PFS) and overall survival (OS) were 10.7 (95% confidence intervals [CI]: 8.3-13.7), 7.3 (95% CI: 5.1-8.6), 5.8 (95% CI: 3.8-7.8) and 34 (95% CI: 28.5-39.8), 22.4 (95% CI: 16-32.1), 18.3 (95% CI: 12.4-26.4) months for first, second and third line, respectively. Efficacy of sunitinib and pazopanib in 1st-line were similar. The mean total cost/patient was 35,012.2 Euros (standard deviation [SD]: 28,971.5). Conclusions: Our study confirms previous real-world data suggesting that continuing advances in the treatment of mRCC produce favorable outcomes in everyday practice. Pharmacoeconomic analyses are important for cost-effective utilization of emerging novel therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Farmacoeconomia , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/economia , Carcinoma de Células Renais/economia , Análise Custo-Benefício , Intervalo Livre de Doença , Feminino , Seguimentos , Grécia , Humanos , Indazóis , Neoplasias Renais/economia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/economia , Metástase Neoplásica , Padrões de Prática Médica/estatística & dados numéricos , Pirimidinas/administração & dosagem , Pirimidinas/economia , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Sulfonamidas/economia , Sunitinibe/administração & dosagem , Sunitinibe/economia , Taxa de Sobrevida
19.
Eur J Med Chem ; 143: 621-631, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29216561

RESUMO

Anthraquinone type compounds, especially di-substituted amino alkylamino anthraquinones have been widely studied as immunosuppressants. The anthraquinone ring is part of mitoxandrone that has been used for the treatment of multiple sclerosis (MS) and several types of tumors. A desired approach for the treatment of MS would be the immunosuppression and elimination of specific T cells that are responsible for the induction of the disease. Herein, the development of a peptide compound bearing an anthraquinone derivative with the potential to specifically destroy the encephalitogenic T cells responsible for the onset of MS is described. The compound consists of the myelin basic protein (MBP) 85-99 immunodominant epitope (MBP85-99) coupled to an anthraquinone type molecule (AQ) via a disulfide (S-S) and 6 amino hexanoic acid (Ahx) residues (AQ-S-S-(Ahx)6MBP85-99). AQ-S-S-(Ahx)6MBP85-99 could bind to HLA II DRB1*-1501 antigen with reasonable affinity (IC50 of 56 nM) The compound was localized to the nucleus of Jurkat cells (an immortalized line of human T lymphocytes) 10 min after its addition to the medium and resulted in lowered Bcl-2 levels (apoptosis). Entrance of the compound was abolished when cells were pre-treated with cisplatin, an inhibitor of thioredoxin reductase. Accordingly, levels of free thiols were elevated in the culture supernatants of Jurkat cells exposed to N-succinimidyl 3-(2-pyridyldithio) propionate coupled to (Ahx)6MBP85-99 via a disulphide (SPDP-S-S-(Ahx)6MBP85-99) but returned to normal after exposure to cisplatin. These results raise the possibility of AQ-S-S-(Ahx)6MBP85-99 being used as an eliminator of encephalitogenic T cells via implication of the thioredoxin system for the generation of the toxic, thiol-containing moiety (AQ-SH). Future experiments would ideally determine whether SPDP-S-S-(Ahx)6MBP85-99 could incorporate into HLA II DRB1*-1501 tetramers and neutralize encephalitogenic T cell lines sensitized to MBP85-99.


Assuntos
Antraquinonas/farmacologia , Desenho de Fármacos , Epitopos/farmacologia , Terapia de Imunossupressão , Proteína Básica da Mielina/farmacologia , Fragmentos de Peptídeos/farmacologia , Linfócitos T/efeitos dos fármacos , Antraquinonas/síntese química , Antraquinonas/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Epitopos/química , Células HEK293 , Humanos , Células Jurkat , Estrutura Molecular , Proteína Básica da Mielina/química , Fragmentos de Peptídeos/química , Relação Estrutura-Atividade
20.
Cancer Genomics Proteomics ; 15(2): 127-141, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29496692

RESUMO

BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) are critically implicated in cancer metastasis and chemoresistance. Herein, we investigated integrin-linked kinase (ILK)'s role in human colon cancer (CRC) progression and chemoresistance in relation to EMT and CSC markers. PATIENTS AND METHODS: Expression of ILK, EMT and CSC markers were evaluated by immunohistochemistry in 149 CRC samples. We also generated colon cancer cells resistant to 5-FU and oxaliplatin and studied the effect of ILK inhibition on drug response by MTT assay and on EMT and CSC markers' expression. RESULTS: ILK expression in human CRC correlates with EMT and CSC markers and is associated with metastasis and chemoresistance. ILK inhibition increases sensitivity of resistant cells to 5-FU and oxaliplatin and reduces the levels of EMT and CSC markers in 5-FU resistant cells. CONCLUSION: ILK overexpression in human CRC associates with EMT and CSC traits, contributing to tumor progression and chemoresistance.


Assuntos
Neoplasias Colorretais/enzimologia , Células-Tronco Neoplásicas/enzimologia , Proteínas Serina-Treonina Quinases/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Células CACO-2 , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Células HT29 , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
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