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1.
Anticancer Res ; 40(9): 4989-4999, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878787

RESUMO

BACKGROUND/AIM: Epithelial to mesenchymal transition (EMT) is a cellular process that facilitates cancer metastasis. Therefore, therapeutic approaches that target EMT have garnered increasing attention. The present study aimed to examine the in vitro effects of ephemeranthol A on cell death, migration, and EMT of lung cancer cells. MATERIALS AND METHODS: Ephemeranthol A was isolated from Dendrobium infundibulum. Non-small cell lung cancer cells H460 were treated with ephemeranthol A and apoptosis was evaluated by Hoechst 33342 staining. Anoikis resistance was determined by soft agar assay. Wound healing assay was performed to test the migration. The regulatory proteins of apoptosis and cell motility were determined by western blot. RESULTS: Treatment with ephemeranthol A resulted in a concentration-dependent cell apoptosis. At non-toxic concentrations, the compound could inhibit anchorage-independent growth of the cancer cells, as indicated by the decreased colony size and number. Ephemeranthol A also exhibited an inhibitory effect on migration. We further found that ephemeranthol A exerts its antimetastatic effects via inhibition of EMT, as indicated by the markedly decrease of N-cadherin, vimentin, and Slug. Furthermore, the compound suppressed the activation of focal adhesion kinase (FAK) and protein kinase B (Akt) proteins, which are key regulators of cell migration. As for the anticancer activity, ephemeranthol A induced apoptosis by decreasing Bcl-2 followed by the activation of caspase 3 and caspase 9. CONCLUSION: The pro-apoptotic and anti-migratory effects of ephemeranthol A on human lung cancer cells support its use for the development of novel anticancer therapies.


Assuntos
Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Neoplasias Pulmonares/patologia , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dendrobium/química , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Estrutura Molecular , Fenantrenos/química
2.
Life Sci ; 259: 118389, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898522

RESUMO

AIMS: Adenosine triphosphate (ATP) is released at a high concentration in the tumor microenvironment. The overexpression of ectonucleotidases in non-small-cell lung cancer (NSCLC), metabolizing ΑΤP to the immunosuppressive adenosine, is studied. MATERIALS AND METHODS: We examined the expression of the ectonucleotidases CD73 and CD39 in NSCLC in parallel with immunological parameters and markers of hypoxia and anaerobic metabolism. In vitro experiments with A549 and H1299 lung cancer cell lines were also conducted. RESULTS: CD73 and CD39 were not expressed by normal bronchial and alveolar epithelium. In contrast, these were overexpressed by cancer cells, cancer-associated fibroblasts (CAFs), and tumor-infiltrating lymphocytes (TILs). High CD73 cancer cell expression was directly linked with lactate dehydrogenase LDH5 and with hypoxia-inducible factor HIF1α expression by cancer cells. The expression of CD39 by CAFs was directly linked with PD-L1 expression by cancer cells. A significant abundance of FOXP3+ and PD-1+ TILs was noted in tumors with high CD73 and CD39 stroma expression. In in vitro experiments, hypoxia and acidity induced CD73 mRNA and protein levels in cancer cell lines. Exposure of cancer cell lines to adenosine induced the expression of PD-L1 and LDHA mRNA and protein levels. CONCLUSION: Ectonucleotidases are up-regulated in cancer cells, CAFs, and TILs in lung tumors. Such overexpression is linked with regulatory TIL-phenotype and PD-L1 up-regulation by cancer cells. Overexpression of LDH5 is up-regulated by adenosine, creating a vicious cycle, as the high amounts of ATP produced by LDH5-mediated anaerobic glycolysis promote the production of adenosine by a tumor microenvironment rich in ectonucleotidases.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Hipóxia/etiologia , Neoplasias Pulmonares/metabolismo , Adenosina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/metabolismo , Tolerância Imunológica , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade
3.
N Engl J Med ; 383(14): 1328-1339, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32997907

RESUMO

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida
4.
PLoS One ; 15(8): e0232917, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810161

RESUMO

In human lung cancer progression, the EMT process is characterized by the transformation of cancer cells into invasive forms that migrate to other organs. Targeting to EMT-related molecules is emerging as a novel therapeutic approach for the prevention of lung cancer cell migration and invasion. Traf2- and Nck-interacting kinase (TNIK) has recently been considered as an anti-proliferative target molecule to regulate the Wnt signaling pathway in several types of cancer cells. In the present study, we evaluated the inhibitory effect of a tyrosine kinase inhibitor sunitinib and the integrin-αⅤß3 targeted cyclic peptide (cRGDfK) on EMT in human lung cancer cells. Sunitinib strongly inhibited the TGF-ß1-activated EMT through suppression of Wnt signaling, Smad and non-Smad signaling pathways. In addition, the cRGDfK also inhibited the expression of TGFß1-induced mesenchymal marker genes and proteins. The anti-EMT effect of sunitinib was enhanced when cRGDfK was treated together. When sunitinib was treated with cRGDfK, the mRNA and protein expression levels of mesenchymal markers were decreased compared to the treatment with sunitinib alone. Co-treatment of cRGDfK has shown the potential to improve the efficacy of anticancer agents in combination with therapeutic agents that may be toxic at high concentrations. These results provide new and improved therapies for treating and preventing EMT-related disorders, such as lung fibrosis and cancer metastasis, and relapse.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Sunitinibe/administração & dosagem , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Células A549 , Trifosfato de Adenosina/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Smad/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
5.
Medicine (Baltimore) ; 99(34): e21369, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846757

RESUMO

Although treatments have improved significantly in recent years, the prognosis of patients with non-small cell lung cancer (NSCLC) remains poor. miR-335 has been demonstrated to play the antitumor role in several cancer types. Its expression was reduced in NSCLC tissues relative to noncancerous adjacent tissues. Furthermore, downregulation of miR-335 in A459 lung cancer cells promoted cell proliferation. In the present study, we aimed to investigate the clinical significance and prognostic value of miR-335 in NSCLC.The lung cancer tissues and adjacent nontumor lung tissues were obtained from 131 patients who underwent the primary surgical resection at Lianyungang First People's Hospital. Student t test was used to distinguish differences between groups. χ test was involved for analysis of clinicopathological data. The overall survival was analyzed by the Kaplan-Meier method and the log rank test. Multiple Cox proportional hazards regression analysis was carried out to identify the independent factors that had a significant impact on patient survival.miR-335 was significantly lower in NSCLC samples compared to non-cancerous samples (P < .001). The expression level of miR-335 was significantly correlated with tumor histology (P = .028), lymph node metastasis (P = .002), differentiation degree (P < .001), and pathological TNM stage (P < .001). The log-rank test indicated that patients with decreased miR-335 expression experienced poor overall survival in NSCLC (P = .029).The results of the present study indicated that miR-335 was down-expressed in NSCLC, and is associated with tumor progression and poor prognosis, suggesting that the expression of miR-335 might be an independent prognostic factor of overall survival in patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , China/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
PLoS One ; 15(8): e0238155, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841278

RESUMO

Non-small cell lung cancer (NSCLC), one of the leading causes of cancer-related death, has a low 5-year survival rate owing to the inevitable acquired resistance toward antitumor drugs, platinum-based chemotherapy, and targeted therapy. Epidermal growth factor (EGF)-EGF receptor (EGFR) signaling activates downstream events leading to phospholipase C/inositol trisphosphate (IP3)/Ca2+ release from IP3-sensitive Ca2+ stores to modulate cell proliferation, motility, and invasion. However, the role of EGFR-mediated Ca2+ signaling in acquired drug resistance is not fully understood. Here, we analyzed alterations of intracellular Ca2+ ([Ca2+]i) responses between gefitinib-sensitive NSCLC PC-9 cells and gefitinib-resistant NSCLC PC-9/GR cells, and we found that acute EGF treatment elicited intracellular Ca2+ ([Ca2+]i) oscillations in PC-9 cells but not in PC-9/GR cells. PC-9/GR cells presented a more sustained basal [Ca2+]i level, lower endoplasmic reticulum Ca2+ level, and higher spontaneous extracellular Ca2+ ([Ca2+]e) influx than PC-9 cells. Notably, restricting [Ca2+]e in both cell types induced identical [Ca2+]i oscillations, dependent on phospholipase C and EGFR activation. Consequently, restricting [Ca2+]e in PC-9/GR cells upregulated gefitinib-mediated poly (ADP-ribose) polymerase cleavage, an increase in Bax/Bcl-2 ratio, cytotoxicity, and apoptosis. In addition, nuclear factor of activated T cell (NFAT1) induction in response to EGF was inhibited by gefitinib in PC-9 cells, whereas EGF-mediated NFAT1 induction in PC-9/GR cells was sustained regardless of gefitinib treatment. Restricting [Ca2+]e in PC-9/GR cells significantly reduced EGF-mediated NFAT1 induction. These findings indicate that spontaneous [Ca2+]e influx in NSCLC cells plays a pivotal role in developing acquired drug resistance and suggest that restricting [Ca2+]e may be a potential strategy for modulating drug-sensitivity.


Assuntos
Antineoplásicos/farmacologia , Sinalização do Cálcio , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , Estrenos/farmacologia , Humanos , Fatores de Transcrição NFATC/biossíntese , Pirrolidinonas/farmacologia , Fosfolipases Tipo C/antagonistas & inibidores
7.
J Cancer Res Clin Oncol ; 146(10): 2621-2630, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32661602

RESUMO

PURPOSE: The epithelial-to-mesenchymal transition (EMT) phenotype-based subsets of circulating tumor cells (CTCs) might be predictors of tumor progression. We evaluated the clinical properties of different phenotypic CTCs in patients with non-small cell lung cancer (NSCLC). Secondly, we explored the association between different phenotypic CTCs and the uptake of 18F-fluorodeoxyglucose (FDG) by the primary tumor on a positron emission tomographic (PET) scan. METHODS: Venous blood samples from 34 pathologically confirmed Stage IIB-IVB NSCLC patients were collected prospectively. CTCs were immunoassayed using a SE-i·FISH®CTC kit. We identified CTCs into cytokeratin positive (CK+) and cytokeratin negative (CK-) phenotypes. CTC classifications were correlated with the maximum standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Overall survival (OS) and progression-free survival (PFS) curves were produced using the Kaplan-Meier method. RESULTS: CTCs were detected in 91.2% of NSCLC patients. CTC counting was associated with TNM stage (P = 0.014) and distant metastasis (P = 0.007). The number of CK-CTCs was also positively associated with TNM stage (P = 0.022) and distant metastasis (P = 0.007). Both total CTC counting and CK-CTC counting did not show association with SUVmax value (P = 0.959, P = 0.903). Kaplan-Meier survival analysis demonstrated that patients with ≥ 7 CTCs had shorter OS (P = 0.003) and PFS (P = 0.001) relative to patients with < 7 CTCs). Notably, the number of CK-CTCs can act as independent risk factors for PFS (P = 0.044) and OS (P = 0.043) in NSCLC patients. However, SUVmax value was not associated with OS (P = 0.895) and PFS (P = 0.686). CONCLUSION: The CTC subpopulations could be useful evidence for testing metastasis and prognosis in NSCLC patients. The SUVmax value of the primary tumor was not related to prognosis in patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Fluordesoxiglucose F18/farmacocinética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/metabolismo , Fenótipo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos
8.
Life Sci ; 257: 118040, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622943

RESUMO

AIMS: Timosaponin AIII (TAIII), an active component with anti-tumor activity from Anemarrhena asphodeloides Bunge, can induce both autophagy and apoptosis of cancer cells. The present study aimed to reveal the promoting or inhibiting role of TAIII-induced autophagy on TAIII-induced apoptosis, to determine the respective upstream signaling pathways for TAIII-induced autophagy and apoptosis; and to observe the therapeutic potential of TAIII in human non-small cell lung cancer in vivo. METHODS AND MATERIALS: WST-1 assay was used to determine the effect of TAIII on cell growth and proliferation. Apoptosis was detected by DAPI staining and flow cytometry. Autophagy was verified by immunofluorescence and transmission electron microscopy. Western blot was used to determine the levels of protein expression. Furthermore, the anti-tumor activity of TAIII was observed in nude mice. KEY FINDINGS: TAIII at high concentrations from 10 µM to 30 µM induced both autophagy and apoptosis in human non-small cell lung cancer cells in a time- and concentration-dependent manner. TAIII at low concentration (1 µM) only induced autophagy. The AMP-activated protein kinase (AMPK) signaling pathway was identified to be responsible for TAIII-induced autophagy both at high or low concentrations. The MAPK/Erk1/2 signaling pathway was identified to be responsible for TAIII-induced apoptosis at the high concentration (20 µM). TAIII-induced autophagy protected cancer cells from apoptosis, and combination of TAIII and autophagy inhibitor showed higher anti-cancer activity.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Saponinas/farmacologia , Esteroides/farmacologia , Células A549 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antineoplásicos , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Saponinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esteroides/metabolismo
9.
Anticancer Res ; 40(6): 3239-3246, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487618

RESUMO

BACKGROUND/AIM: Non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH) is implicated in correct chromosome condensation and segregation during mitosis. However, the functional role of NCAPH in the pathogenesis of non-small-cell lung cancer (NSCLC) remains unclear. The aim of this study was to elucidate the role of NCAPH in NSCLC cells. MATERIALS AND METHODS: A549 and H1299 NSCLC cells were transfected with small-interfering RNA (siRNA) against NCAPH. Subsequently, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony-formation assay and flow cytometry analysis were performed to reveal the role of NCAPH in NSCLC cells. In addition, migration and invasion assay were also performed. RESULTS: NCAPH knockdown inhibited cell proliferation, induced cell-cycle arrest at G2/M phase, and prevented colony formation, migration and invasion by NSCLC cells. CONCLUSION: NCAPH is involved in NSCLC progression and development, and may be a potential therapeutic target for NSCLC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Nucleares/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Pontos de Checagem do Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Invasividade Neoplásica , Proteínas Nucleares/biossíntese , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transfecção , Regulação para Cima
10.
Anticancer Res ; 40(6): 3355-3360, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487631

RESUMO

BACKGROUND/AIM: Proliferation biomarkers such as MIB-1 are strong predictors of clinical outcome and response to therapy in patients with non-small-cell lung cancer, but they require histological examination. In this work, we present a classification model to predict MIB-1 expression based on clinical parameters from positron emission tomography. PATIENTS AND METHODS: We retrospectively evaluated 78 patients with histology-proven non-small-cell lung cancer (NSCLC) who underwent 18F-FDG-PET/CT for clinical examination. We stratified the population into a low and high proliferation group using MIB-1=25% as cut-off value. We built a predictive model based on binary classification trees to estimate the group label from the maximum standardized uptake value (SUVmax) and lesion diameter. RESULTS: The proposed model showed ability to predict the correct proliferation group with overall accuracy >82% (78% and 86% for the low- and high-proliferation group, respectively). CONCLUSION: Our results indicate that radiotracer activity evaluated via SUVmax and lesion diameter are correlated with tumour proliferation index MIB-1.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Fluordesoxiglucose F18 , Antígeno Ki-67/biossíntese , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/fisiologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Estudos Retrospectivos
11.
PLoS One ; 15(6): e0234268, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497150

RESUMO

Annexin A1 (anxA1) is an immunomodulatory protein that has been proposed as a tumor vascular target for antitumor biologic agents, yet to date the vascular expression of anxA1 in specific tumor indications has not been systematically assessed. Attempts to evaluate vascular anxA1 expression by immunohistochemistry are complicated by a lack of available antibodies that are both specific for anxA1 and bind the N-terminal-truncated form of anxA1 that has previously been identified in tumor vasculature. To study the vascular expression pattern of anxA1 in non-small-cell lung carcinoma (NSCLC), we isolated an antibody capable of binding N-terminal-truncated anxA127-346 and employed it in immunohistochemical studies of human lung specimens. Lung tumor specimens evaluated with this antibody revealed vascular (endothelial) anxA1 expression in five of eight tumor samples studied, but no vascular anxA1 expression was observed in normal lung tissue. Tumor microarray analysis further demonstrated positive vascular staining for anxA1 in 30 of 80 NSCLC samples, and positive staining of neoplastic cells was observed in 54 of 80 samples. No correlation was observed between vascular and parenchymal anxA1 expression. Two rodent tumor models, B16-F10 and Py230, were determined to have upregulated anxA1 expression in the intratumoral vasculature. These data validate anxA1 as a potential vascular anti-tumor target in a subset of human lung tumors and identify rodent models which demonstrate anxA1 expression in tumor vasculature.


Assuntos
Anexina A1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Regulação para Cima , Animais , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Camundongos
12.
Nucleic Acids Res ; 48(13): 7027-7040, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32542340

RESUMO

Methylation of miRNAs at the 2'-hydroxyl group on the ribose at 3'-end (2'-O-methylation, 2'Ome) is critical for miRNA function in plants and Drosophila. Whether this methylation phenomenon exists for mammalian miRNA remains unknown. Through LC-MS/MS analysis, we discover that majority of miR-21-5p isolated from human non-small cell lung cancer (NSCLC) tissue possesses 3'-terminal 2'Ome. Predominant 3'-terminal 2'Ome of miR-21-5p in cancer tissue is confirmed by qRT-PCR and northern blot after oxidation/ß-elimination procedure. Cancerous and the paired non-cancerous lung tissue miRNAs display different pattern of 3'-terminal 2'Ome. We further identify HENMT1 as the methyltransferase responsible for 3'-terminal 2'Ome of mammalian miRNAs. Compared to non-methylated miR-21-5p, methylated miR-21-5p is more resistant to digestion by 3'→5' exoribonuclease polyribonucleotide nucleotidyltransferase 1 (PNPT1) and has higher affinity to Argonaute-2, which may contribute to its higher stability and stronger inhibition on programmed cell death protein 4 (PDCD4) translation, respectively. Our findings reveal HENMT1-mediated 3'-terminal 2'Ome of mammalian miRNAs and highlight its role in enhancing miRNA's stability and function.


Assuntos
Proteínas Argonauta/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Exorribonucleases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metilação , Proteínas de Ligação a RNA/metabolismo
13.
Niger J Clin Pract ; 23(6): 842-847, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32525121

RESUMO

Background: The most widely accepted approach nowadays in nodal staging of non-small cell lung cancer (NSCLC) is the combined use of 18-Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) and endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). However, this approach may not be sufficient, especially for early stages. Aims: Our aim was to assess whether more satisfactory results can be obtained with standardized uptake value maximum lymph node/standardized uptake value mean mediastinal blood pool (SUVmax LN/SUVmean MBP), SUVmax LN/Primary tumor, or a novel cut-off value to SUVmax in this special group. Subjects and Methods: Patients with diagnosed NSCLC and underwent FDG-PET/CT were reviewed retrospectively. 168 LNs of 52 early stage NSCLC patients were evaluated. The LNs identified in surgery/pathology reports were found in the FDG-PET/CT images. Anatomic and metabolic parameters were measured. Statistical analysis was performed by using of MedCalc Statistical Software. Results: Regardless of LNs size; sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of SUVmax >2.5 were 91.5%, 65.9%, 58.2%, and 95.1%, respectively. Optimum cut-off value of SUVmax was >4.0. Sensitivity, specificity, PPV, and NPV were found as 81.0%, 90.0%, 81.0%, and 90.0% respectively. Optimum cut-off value of SUVmax LN/SUVmean MBP was >1.71. Sensitivity, specificity, PPV, and NPV were found as 94.7%, 80.0%, 71.1%, and 96.7%, respectively. Optimum cut-off value of SUVmax LN/Primary tumor was >0.28. Sensitivity, specificity, PPV, and NPV were found as 81.1%, 85.1%, 72.9% and 90.1%, respectively. Conclusion: SUVmax LN/SUVmean MBP >1.71 has higher PPV than currently used, with similar NPV and sensitivity. This can provide increase in the accuracy of combined approach. In this way, faster nodal staging/treatment decisions, cost savings for healthcare system and time saving of medical professionals can be obtained.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Fluordesoxiglucose F18/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Estadiamento de Neoplasias/métodos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Biópsia por Agulha Fina , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Endossonografia/métodos , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Mediastino/patologia , Pessoa de Meia-Idade , Imagem Multimodal , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade
14.
Cell Prolif ; 53(8): e12869, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32597573

RESUMO

OBJECTIVES: Cryptococcus heimaeyensis S20 is found in Antarctica and can produce exopolysaccharides (CHEPS). Here, we explore the anti-tumour effects of CHEPS on non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Cell viability was assessed by CCK8 and colony formation assays. Flow cytometry was used to analyse the cell cycle, cell apoptosis and reactive oxygen species (ROS). Cell autophagy was detected by EGFP-LC3 puncta assay, Lyso-Tracker Red staining and transmission electron microscopy. mRNA and protein levels were analysed by qRT-PCR and Western blot. Related mechanisms were confirmed using appropriate inhibitors or shRNA. In vitro results were further confirmed by a tumour xenograft study. RESULTS: CHEPS inhibited the proliferation of NSCLC cells by inducing S- and G2/M-phase arrest and autophagic cell death, but not apoptosis. CHEPS was less toxic to normal human embryonic lung fibroblasts. CHEPS activated the MAPK pathway in NSCLC cells, and p38 and ERK promoted CHEPS-induced cell death. Further studies showed that p38 and ERK promoted CHEPS-induced NSCLC cell autophagy and ERK promoted CHEPS-induced S- and G2/M-phase arrest. ROS were induced by CHEPS. A ROS scavenger attenuated CHEPS-induced p38 and ERK activation, autophagy and cell death. Finally, CHEPS reduced orthotopic lung tumour growth without organ-related toxicity. CHEPS also induced ROS, activated p38 and ERK, and triggered autophagy in vivo. CONCLUSIONS: CHEPS induces autophagic cell death and S- and G2/M-phase arrest in NSCLC cells via ROS/p38 and ROS/ERK signalling.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cryptococcus/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Morte Celular Autofágica/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Cryptococcus/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Gene ; 755: 144886, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32534055

RESUMO

Non-small cell lung cancer (NSCLC) is a common lung cancer with high mortality worldwide. Cisplatin (DDP) resistance is a huge limitation for NSCLC therapy. FGD5 antisense RNA 1 (FGD5-AS1) was recognized as a significant cancer cell regulator. However, the molecular mechanism of FGD5-AS1 in cisplatin resistance of NSCLC cells is poorly understood. FGD5-AS1 and WEE1 expression were up-regulated in DDP-resistant tumors and cells compared with DDP-sensitive ones. Interestingly, down-regulation of FGD5-AS1 or WEE1 inhibited cell proliferation, migration, invasion, autophagy and stimulated cell apoptosis in NSCLC DDP-resistant cells. What's more, restoration of WEE1 abrogated FGD5-AS1 silencing-induced suppression on cell proliferation, migration, invasion, autophagy and promotion on cell apoptosis in NSCLC DDP-resistant cells. Next, we discovered that FGD5-AS1 was able to enhance WEE1 expression by interacting with miR-140-5p. Furthermore, FGD5-AS1 silencing restrained tumor growth of cisplatin-resistant mice. Overexpression of FGD5-AS1 accelerated cell proliferation, migration, invasion and autophagy by enhancing cisplatin resistance against NSCLC cells through miR-140-5p/WEE1 axis, presenting promising biomarkers for the diagnosis of DDP-resistant NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Cisplatino/farmacologia , Fatores de Troca do Nucleotídeo Guanina/genética , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/metabolismo , Proteínas Tirosina Quinases/metabolismo , RNA Antissenso/metabolismo , Células A549 , Adulto , Animais , Apoptose/genética , Autofagia/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/genética , RNA Antissenso/biossíntese , RNA Antissenso/genética , RNA Longo não Codificante/genética
16.
Life Sci ; 256: 117923, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522567

RESUMO

AIMS: Liver kinase B1 (LKB1) deficiency is associated with reduced expression of programmed death ligand 1 (PD-L1) and inferior clinical outcomes of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC). This study aimed to investigate the mechanism by which LKB1 regulates PD-L1 expression and its role in programmed death 1 (PD-1) blockade therapy in NSCLC. MAIN METHODS: The impact of LKB1 on PD-L1 was assessed by western blot, qRT-PCR and immunohistochemistry in NSCLC. Activators/inhibitors of AMPK and NRF2 were applied to explore the mechanisms underlying the regulation of PD-L1 by LKB1. Efficiency of combined application of metformin and PD-1 blockade was evaluated in immunocompetent C57BL/6 mice. KEY FINDINGS: A remarkable positive correlation between LKB1 and PD-L1 expression was demonstrated in NSCLC tissues. Knockdown of LKB1 decreased PD-L1 in TC-1 cells, whereas overexpression of LKB1 increased PD-L1 in A549 cells. We further characterized that AMPK mediated the upregulation of PD-L1 by LKB1. Inhibition of AMPK or NRF2 markedly reduced PD-L1 in LKB1-intact NSCLC cells. In contrast, activation of AMPK or NRF2 reversed PD-L1 expression in LKB1-deficient NSCLC cells. Combined administration of metformin and anti-PD-1 antibody efficiently inhibited the growth of LKB1-intact tumors, whereas no obvious suppression was observed in LKB1-deficient tumors. SIGNIFICANCE: These findings demonstrated that LKB1 upregulates PD-L1 expression in NSCLC by activating the AMPK and KEAP1/NRF2 signaling. Activation of LKB1-AMPK with metformin improves the therapeutic effect of PD-1 blockade in NSCLC with wild-type LKB1.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Metformina/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Metformina/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais , Ativação Transcricional , Regulação para Cima
17.
J Cancer Res Clin Oncol ; 146(10): 2595-2605, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32494919

RESUMO

PURPOSE: The combined small-cell lung cancer (c-SCLC) is rare and has unique clinicopathological futures. The aim of this study is to investigate 18F-FDG PET/CT parameters and clinicopathological factors that influence the prognosis of c-SCLC. METHODS: Between November 2005 and October 2014, surgical-resected tumor samples from c-SCLC patients who received preoperative 18F-FDG PET/CT examination were retrospectively reviewed. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were used to evaluate metabolic parameters in primary tumors. The survivals were evaluated with the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate potential prognostic factors. RESULTS: Thirty-one patients were enrolled, with a median age of 62 (range: 35 - 79) years. The most common mixed component was squamous cell carcinoma (SCC, n = 12), followed by large-cell carcinoma (LCC, n = 7), adenocarcinoma (AC, n = 6), spindle cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and atypical carcinoid (n = 1). The median follow-up period was 53.0 (11.0-142.0) months; the 5-year overall survival (OS) and progression-free survival(PFS) rate were 48.4% and 35.5%, respectively. Univariate survival analysis showed that gender, smoking history, tumor location were associated with PFS (P = 0.036, P = 0.043, P = 0.048), SUVmax and TNM stage were closely related to PFS in both Mixed SCC and non-SCC component groups (P = 0.007, P = 0.048). SUVmax, smoking history, tumor size and mixed SCC component were influencing factors of OS in patients (P = 0.040, P = 0.041, P = 0.046, P = 0.029). Multivariate survival analysis confirmed that TNM stage (HR = 2.885, 95%CI: 1.323-6.289, P = 0.008) was the most significantly influential factor for PFS. High SUVmax value (HR = 9.338, 95%CI: 2.426-35.938, P = 0.001) and mixed SCC component (HR = 0.155, 95%CI: 0.045-0.530, P = 0.003) were poor predictors for OS. CONCLUSION: Surgical-resected c-SCLCs have a relatively good prognosis. TNM stage is the most significant factor influencing disease progression in surgical-resected c-SCLCs. SUVmax and mixed NSCLC components within c-SCLCs had a considerable influence on the survival. Both high SUVmax and mixed SCC component are poor predictors for patients with c-SCLCs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Fluordesoxiglucose F18/farmacocinética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Análise de Sobrevida
18.
Cancer Sci ; 111(9): 3210-3221, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32519357

RESUMO

Non-small-cell lung cancer (NSCLC) is the leading global cause of cancer-related death. Due to the lack of reliable diagnostic or prognostic biomarkers, the prognosis of NSCLC remains poor. Consequently, there is an urgent need to explore the mechanisms underlying this condition in order to identify effective biomarkers. G-protein-signaling modulator 2 (GPSM2) is widely recognized as a determinant of mitotic spindle orientation. However, its role in cancer, especially NSCLC, remains uncertain. In this study, we found that GPSM2 was downregulated in NSCLC tissues and was correlated with a poor prognosis. Furthermore, the knockdown of GPSM2 promoted NSCLC cell metastasis in vitro and in vivo and accelerated the process of epithelial-mesenchymal transition (EMT). Mechanistically, we showed that silencing GPSM2 induced cell metastasis and EMT through the ERK/glycogen synthase kinase-3ß/Snail pathway. These results confirm that GPSM2 plays an important role in NSCLC. Moreover, GPSM2, as an independent prognostic factor, could be a potential prognostic biomarker and drug target for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Fatores de Transcrição da Família Snail/genética , Adulto , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Bases de Dados Genéticas , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Fatores de Transcrição da Família Snail/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cancer Sci ; 111(9): 3174-3183, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32539182

RESUMO

Programmed cell death-ligand 1 (PD-L1) expressed on cancer cells can cause immune escape of non-small-cell lung cancer (NSCLC). Elucidation of the regulatory mechanisms of the PD-L1 expression is a prerequisite for establishing new tumor immunotherapy strategies. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a regulator of cellular signaling transduction that is aberrantly expressed in NSCLC. However, it is not known whether UCHL1 regulates the expression of PD-L1 in NSCLC cells. In the present study, we found that UCHL1 promotes the expression of PD-L1 in NSCLC cell lines. In addition, UCHL1 expressed in NSCLC cells inhibited activation of Jurkat cells through upregulation of PD-L1 expression in in vitro experiments. Moreover, UCHL1 upregulates PD-L1 expression through facilitating activation of the AKT-P65 signaling pathway. In conclusion, these results indicated that UCHL1 promoted PD-L1 expression in NSCLC cells. This finding implied that inhibition of UCHL1 might suppress immune escape of NSCLC through downregulation of PD-L1 expression in NSCLC cells.


Assuntos
Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ubiquitina Tiolesterase/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Imunomodulação , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Transcrição RelA/metabolismo
20.
Toxicol Appl Pharmacol ; 401: 115112, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32540278

RESUMO

Cancer stem cells (CSCs) accounts for recurrence and resistance to chemotherapy in various tumors. Efficacy of chemotherapeutic drugs is limited by tumor stromal barriers, which hinder their penetration into deep tumor sites. We have earlier shown telmisartan (Tel) pretreatment prior to Docetaxel (DTX) administration enhances anti-cancer effects in non-small cell lung cancer (NSCLC). Herein, we demonstrated for the first time the efficacy of Docetaxel liposomes (DTXPL) in combination with Tel in 3D cultures of H460 cells by using polysaccharide-based hydrogels (TheWell Biosciences) and also in xenograft model of DTX resistant H460 derived CD133+ lung tumors. DTXPL and Tel combination showed enhanced cytotoxicity in H460 WT 3D cultures by two folds. In H460 3D cultures, Tel pretreatment showed increased liposomal uptake. DTXPL and Tel combination treated tumors showed reduction in tumor volume (p < .001), increased apoptosis and downregulation of CSC markers (p < .01) in H460 WT and DTX resistant CD133+ xenograft models.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Células-Tronco Neoplásicas/efeitos dos fármacos , Telmisartan/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Feminino , Humanos , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo
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