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1.
Anticancer Res ; 41(2): 757-764, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517280

RESUMO

BACKGROUND/AIM: Improvement of the efficacy of radiotherapy for lung cancer and glioblastoma is urgently needed. MATERIALS AND METHODS: We synthesized several novel DNA methyltransferase inhibitors and evaluated their potentials as possible radiosensitizers. Eleven non-nucleoside compounds were synthesized and evaluated along with one known compound using human lung cancer (A549) and glioblastoma (U373MG) cells. Cytotoxicity and radiosensitizing effects were evaluated using clonogenic assay. Sensitizer enhancement ratios at a survival fraction of 0.5 were calculated, and statistical analysis was performed using the ratio paired t-test. The inhibitory effects of three selected compounds on the activity of DNA methyltransferase 1 (DNMT1) and the pharmacokinetic profiles were analyzed. RESULTS: All twelve compounds demonstrated various levels of cytotoxicity. Of the twelve compounds, eleven and eight compounds radiosensitized A549 and U373MG cells, respectively, with at least marginal significance (p<0.10). The sensitizer enhancement ratios in A549 and U373MG ranged 1.166-2.537 and 1.083-1.743 among compounds with radiosensitizing effects, respectively. The three selected compounds inhibited DNMT1 activity by 26.5-78.5%. Elimination half-lives ranged from 0.3 to 1.3 h. CONCLUSION: Novel DNA methyltransferase inhibitors with significant radiosensitizing capacity and improved biostability were synthesized. These materials will serve as a basis for the development of novel radiosensitizers.


Assuntos
Neoplasias Encefálicas/enzimologia , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Inibidores Enzimáticos/farmacologia , Glioblastoma/enzimologia , Neoplasias Pulmonares/enzimologia , Radiossensibilizantes/farmacologia , Células A549 , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Regulação para Baixo , Inibidores Enzimáticos/síntese química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/terapia , Humanos , Neoplasias Pulmonares/terapia , Estrutura Molecular , Radiossensibilizantes/síntese química
2.
Biomed Pharmacother ; 133: 111079, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378976

RESUMO

Non-small cell lung cancer (NSCLC) remains by far the single most common malignancy of lung cancer which causes more and more mortality in recent years. NSCLC accounts for more than 80 % of lung cancers, and the vast majority of patients were found to be in advanced inoperable stages. Chemotherapy used to be the main treatment for NSCLC, but due to its obvious side effects. Chemotherapy gradually withdrew from the stage of history. In recent years, cellular and molecular biotechnology has developed rapidly, and researchers have begun to target key genes and regulatory molecules for treatment. Targeted drugs have also emerged. The purpose of this review is to introduce important research achievements in recent years and the treatment progress of new drugs.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Medicina de Precisão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Resultado do Tratamento
3.
Anticancer Res ; 40(11): 6039-6049, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109542

RESUMO

BACKGROUND/AIM: Previously, we reported the identification of a cytotoxic chemotype compound CC-I (1a), a derivative of thiobarbituric acid. We also reported the anticancer activity of a series of novel thio- and seleno-barbituric acid analogs. MATERIALS AND METHODS: We herein evaluated the effect of 1a and its modified compounds on in vitro and in vivo lung cancer models. RESULTS: The compounds 1b and 2a showed more potent cytotoxicity than 1a to lung cancer cells. Moreover, 1b did not have any cytotoxicity on normal cells, such as fibroblasts. In the human lung cancer A549 mouse tumor xenograft model, 1b and 2a showed more pronounced antitumor effects than 1a In the A549 lung cancer cells, 1a induced cell death mainly via JNK and p38 MAPK activation. However, compound 1b and 2a induced lung cancer cell death mostly through JNK activation. CONCLUSION: The results suggest that 1b and 2a can be useful therapeutic agents for lung cancer.


Assuntos
Barbitúricos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Tiobarbitúricos/uso terapêutico , Células A549 , Barbitúricos/síntese química , Barbitúricos/química , Barbitúricos/farmacologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Tiobarbitúricos/química , Tiobarbitúricos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
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
5.
J Cancer Res Ther ; 16(4): 718-725, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930109

RESUMO

Aim of Study: There were many reports published on the relationship between glutathione S-transferase T1 (GSTT1) null/presence gene polymorphism and the risk of lung cancer in these years. In previous, we conducted a meta-analysis to evaluate the relationship between GSTT1 null/presence gene polymorphism and the risk of lung cancer. This study was conducted to update it. Materials and Methods: The association studies were identified from PubMed and Cochrane Library on March 1, 2016. Results: Sixty-three reports were recruited into this meta-analysis for the association of null genotype of GSTT1 with lung cancer susceptibility, consisting of 21,220 patients with lung cancer and 21,496 controls. There was a marked association between GSTT1 null genotype and lung cancer risk in overall populations and in Asians (overall populations: Odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.07-1.28, P = 0.006; Asians: OR = 1.41, 95% CI: 1.23-1.62, P < 0.00001). However, GSTT1 null genotype was not associated with the risk of lung cancer in Caucasians, Brazilian population, and Africans. Conclusion: GSTT1 null genotype is associated with the lung cancer risk in overall populations and in Asians.


Assuntos
Glutationa Transferase/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/etnologia , Polimorfismo Genético , Prognóstico , Fatores de Risco
6.
J Cancer Res Ther ; 16(4): 811-815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930123

RESUMO

Background: Lung cancer is one of the most frequent types of cancer and the leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) being highly expressed in lung cancers. Activation of EGFR through oncogenic mutations leads to upregulation of gene expression that may heighten the inflammatory response in certain situations. EGFR acts as a key regulator and a cellular hub for inflammatory cytokine signaling, thereby promoting tumor cell proliferation, invasion, migration, metastases, and survival. The aim of the present study is to determine the serum cytokines levels and EGFR mutation status in lung cancer patients to investigate the association between the EGFR mutation status and cytokines levels with lung cancer patients. Materials and Methods: Blood and tissue samples of lung cancer patients were collected. The EGFR mutations of lung cancer patients were determined by the immunohistochemistry (IHC) and serum cytokines levels of lung cancer patients were determined using ELISA. Results: Statistically significant association of EGFR mutations with adenocarcinoma subtypes and non-smokers were found (P < 0.05). Lung cancer patients with EGFR mutations had significantly higher tumor necrosis factor-alpha levels when compared to lung cancer patients without EGFR mutations (P < 0.01), and EGFR mutation status was not significantly associated with interleukin-6 levels (P = 0.24). Conclusion: EGFR mutation detection by the IHC method is a potentially useful tool to guide clinicians for personalized treatment of lung cancer patients of adenocarcinoma subtype, and cytokines are good biomarkers for the diagnosis, prognosis, and prediction of treatment responses in lung cancer patients as well as act as therapeutic targets. This study will provide biomarkers for lung cancer diagnosis and treatments.


Assuntos
Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Citocinas/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fator de Necrose Tumoral alfa/sangue
7.
Life Sci ; 258: 118211, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768576

RESUMO

AIMS: Cisplatin is the mainstay of first-line treatment for advanced non-small cell lung cancer (NSCLC). Accumulating evidence suggests that flavonoids inhibit histone deacetylase (HDAC) to mediate their anticancer effect in various cancer types. The study was conducted to investigate the inhibition of HDAC and the modulation of apoptotic and cell cycle regulatory genes by selected flavonoids to potentiate the anticancer effect of cisplatin. MAIN METHODS: Combinations of cisplatin and selected flavonoids were investigated in three NSCLC cell lines (A549, H460, and H1299). Sulforhodamine B assay was used to evaluate cytotoxicity of drug combinations. Western blot analysis was conducted to evaluate histone acetylation. Flow cytometric assays were used to investigate the apoptotic and cell cycle effect. Chromatin immunoprecipitation assay was performed to elucidate the binding of transcription factors to promoters of selected apoptotic and cell cycle regulatory genes. KEY FINDINGS: Apigenin was found to exhibit the strongest HDAC inhibitory effect among all flavonoids tested. Cisplatin-apigenin combination was shown to produce significantly more S phase prolongation and G2/M cell cycle arrest, and apoptosis compared with cisplatin or apigenin alone, by inducing p21 and PUMA, respectively. More pronounced effect was observed in p53-proficient than p53-null NSCLC cells. Mechanistically, apigenin was found to reduce the binding of HDAC1 but increase the association of RNA polymerase II and Sp1 to p21 and PUMA promoters. SIGNIFICANCE: Our findings provide a better insight about the mechanism contributing to the HDAC inhibitory effect of apigenin to potentiate anticancer effect of cisplatin by inducing apoptosis and cell cycle arrest.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Cisplatino/administração & dosagem , Flavonoides/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Neoplasias Pulmonares/enzimologia , Células A549 , Antineoplásicos/química , Apigenina/administração & dosagem , Apigenina/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cisplatino/química , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Flavonoides/química , Inibidores de Histona Desacetilases/química , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia
8.
J Cancer Res Clin Oncol ; 146(10): 2447-2460, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32627077

RESUMO

BACKGROUND: Despite great advances in its early diagnosis and treatment, lung cancer is still an intractable disease and the second leading cause of cancer-related deaths and morbidity in the world. The family of Polo-like kinases (PLKs) consists of five serine/threonine kinases, which have been reported to participate in various human diseases. However, the expression and prognostic value of each PLK in human lung cancer have not been fully understood. This study analyzed mRNA expression and prognostic value of different PLKs in human non-small cell lung cancer (NSCLC). METHODS: First, mRNA expression of PLKs in patients with NSCLC from the Oncomine and the Gene Expression Profiling Interactive Analysis (GEPIA) database was investigated. Then, a Kaplan-Meier plotter was employed for survival analysis. The sequence alteration for PLKs was analyzed using The Cancer Genome Atlas (TCGA) and the cBioPortal database. Additionally, we analyzed the association among different PLKs using the LinkedOmics database. Finally, the enrichment analysis of PLKs was achieved using the DAVID database. RESULTS: The mRNA expression levels of PLK1 and PLK4 were significantly overexpressed, while mRNA expression level of PLK3 was underexpressed in patients with NSCLC. mRNA expressions of PLK1 and PLK4 were significantly and positively related to the tumor stage of NSCLC. Increased expressions of PLK1, PLK4, and PLK5 and decreased expression of PLK2 were attributed to limited overall survival time in NSCLC. PLK1 was positively correlated with PLK4 via the LinkedOmics database. CONCLUSIONS: PLKs are relevant targets for NSCLC treatment, especially PLK1 and PLK4.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Prognóstico , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma
9.
PLoS Biol ; 18(7): e3000778, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678845

RESUMO

The evolution of transformed cancer cells into metastatic tumors is, in part, driven by altered intracellular signaling downstream of receptor tyrosine kinases (RTKs). The surface levels and activity of RTKs are governed mainly through clathrin-mediated endocytosis (CME), endosomal recycling, or degradation. In turn, oncogenic signaling downstream of RTKs can reciprocally regulate endocytic trafficking by creating feedback loops in cells to enhance tumor progression. We previously showed that FCH/F-BAR and Double SH3 Domain-Containing Protein (FCHSD2) has a cancer-cell specific function in regulating CME in non-small-cell lung cancer (NSCLC) cells. Here, we report that FCHSD2 loss impacts recycling of the RTKs, epidermal growth factor receptor (EGFR) and proto-oncogene c-Met (MET), and shunts their trafficking into late endosomes and lysosomal degradation. Notably, FCHSD2 depletion results in the nuclear translocation of active extracellular signal-regulated kinase 1 and 2 (ERK1/2), leading to enhanced transcription and up-regulation of EGFR and MET. The small GTPase, Ras-related protein Rab-7A (Rab7), is essential for the FCHSD2 depletion-induced effects. Correspondingly, FCHSD2 loss correlates to higher tumor grades of NSCLC. Clinically, NSCLC patients expressing high FCHSD2 exhibit elevated survival, whereas patients with high Rab7 expression display decreased survival rates. Our study provides new insight into the molecular nexus for crosstalk between oncogenic signaling and RTK trafficking that controls cancer progression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/metabolismo , Endocitose , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Oncogenes , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Progressão da Doença , Endossomos/metabolismo , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/enzimologia , Transporte Proteico , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores da Transferrina/metabolismo , Regulação para Cima , Proteínas rab de Ligação ao GTP/metabolismo
10.
Anticancer Res ; 40(7): 3857-3863, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620625

RESUMO

BACKGROUND: The aim of this study was to define the alterations in the activity of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in normal and cancerous lung cells. MATERIALS AND METHODS: Lung tissues were taken from 36 patients during surgical resection of cancer. The activities of tested enzymes were measured by spectrofluorometric method (ADH I, ADH II, total ALDH) and photometric method (ADH III, ADH IV, total ADH). RESULTS: The activities of class II and III ADH were significantly lower in lung cancer cells compared to histologically normal lung tissue. CONCLUSION: Reduced activity of isoenzyme class II ADH may affect disorders in retinoic acid biosynthesis, leading to its deficit. Lower ADH III activity may result in depletion of glutathione, and in initiation of oxidative stress, leading to cancer progression. These data suggest that alterations in ADH isoenzyme activities can contribute to carcinogenesis in human lungs.


Assuntos
Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , Neoplasias Pulmonares/enzimologia , Adenocarcinoma de Pulmão/enzimologia , Carcinoma de Células Escamosas/enzimologia , Feminino , Humanos , Isoenzimas/metabolismo , Masculino , Fatores Sexuais
11.
Expert Opin Pharmacother ; 21(13): 1547-1554, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32511029

RESUMO

INTRODUCTION: Approximately 3-7% of advanced non-small cell lung cancers (NSCLC) are driven by an anaplastic lymphoma kinase (ALK) rearrangement. Crizotinib, ceritinib, alectinib, and brigatinib are active ALK inhibitors (ALKi) used to treat this oncogene-driven subset of NSCLC. Resistance occurs with time to ALKi and new therapeutics are being developed. Lorlatinib is an efficacious third-generation ALKi with an ability to overcome resistance mutations that develop with first- or second-generation ALKi. AREAS COVERED: Herein, the authors review the mechanism of action, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of lorlatinib and provide their future perspectives on this drug. EXPERT COMMENTARY: Lorlatinib is a potent ALK and ROS-1 inhibitor that also has activity against many acquired ALK resistance mutations. Clinical trials show the robust systemic and intracranial anti-tumor activity of lorlatinib in ALK rearranged advanced NSCLC. Adverse events of lorlatinib are unique and manageable. These include hypocholesteremia, hypertriglyceridemia, edema, cognitive effects, weight gain, and diarrhea. Loratinib will play an increasing role in the management of ALK-rearranged NSCLC with the optimal sequencing of ALKi undergoing further research.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico/genética , Animais , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias Pulmonares/enzimologia , Resultado do Tratamento
13.
J Pathol ; 251(2): 187-199, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32237123

RESUMO

Despite its efficacy in solid tumours, in particular HER2+ breast cancer, HER2-targeted therapy has given rise to disappointing results in non-small cell lung cancer (NSCLC). With the aim of refining the target population for anti-HER2 therapies in NSCLC, we investigated the relationships between HER2 and the tumour suppressor fragile histidine triad (FHIT) in lung tumour cells. First, we observed a negative correlation between FHIT expression and the activated form of HER2 (pHER2) in NSCLC samples and in lung tumour cell lines. Moreover, the silencing or overexpression of FHIT in lung cell lines led to an increase or decrease of HER2 activity, respectively. We also demonstrated that two anti-HER2 drugs, irbinitinib and trastuzumab, restore a more epithelial phenotype and counteract cell invasiveness and growth of FHIT-silenced tumour cell lines. Finally, we showed that the FHITlow /pHER2high phenotype predicts sensitivity to an anti-HER2 therapy in primary tumour cells from NSCLC patients. Our results show that FHIT regulates the activity of HER2 in lung tumour cells and that FHIT-inactivated tumour cells are sensitive to HER2 inhibitors. A new subclass of patients with NSCLC may be eligible for an anti-HER2 therapy. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Hidrolases Anidrido Ácido/metabolismo , Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/farmacologia , Células A549 , Hidrolases Anidrido Ácido/genética , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Oncogene ; 39(20): 3980-3996, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32238881

RESUMO

Branched-chain α-keto acid dehydrogenase kinase (BCKDK), the key enzyme of branched-chain amino acids (BCAAs) metabolism, has been reported to promote colorectal cancer (CRC) tumorigenesis by upregulating the MEK-ERK signaling pathway. However, the profile of BCKDK in metastatic colorectal cancer (mCRC) remains unknown. Here, we report a novel role of BCKDK in mCRC. BCKDK is upregulated in CRC tissues. Increased BCKDK expression was associated with metastasis and poor clinical prognosis in CRC patients. Knockdown of BCKDK decreased CRC cell migration and invasion ex vivo, and lung metastasis in vivo. BCKDK promoted the epithelial mesenchymal transition (EMT) program, by decreasing the expression of E-cadherin, epithelial marker, and increasing the expression of N-cadherin and Vimentin, which are mesenchymal markers. Moreover, BCKDK-knockdown experiments in combination with phosphoproteomics analysis revealed the potent role of BCKDK in modulating multiple signal transduction pathways, including EMT and metastasis. Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. In summary, the identification of BCKDK as a novel prometastatic factor in human CRC will be beneficial for further diagnostic biomarker studies and suggests novel targeting opportunities.


Assuntos
3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Neoplasias Colorretais/enzimologia , Neoplasias Pulmonares/enzimologia , Proteínas de Neoplasias/metabolismo , Quinases da Família src/metabolismo , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Aminoácidos de Cadeia Ramificada/genética , Animais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias/genética , Fosforilação , Transdução de Sinais/genética , Quinases da Família src/genética
15.
Cancer Treat Rev ; 86: 101996, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32135383

RESUMO

Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies. Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations. Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Receptor ErbB-2/genética , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Amplificação de Genes , Humanos , Imunoconjugados/imunologia , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/biossíntese , Receptor ErbB-2/imunologia
16.
Biochem Pharmacol ; 175: 113914, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173363

RESUMO

Transcriptional coactivators p300 and CBP catalyze the acetylation of lysine residues in histone proteins. Upregulation of p300 and CBP has been associated with lung, colorectal and hepatocellular cancer, indicating an important role of p300 and CBP in tumorigenesis. Recently, the novel p300 and CBP-selective inhibitor A485 became available, which was shown to inhibit proliferation of 124 different cancer cell lines. Here, we found that downregulation of EP300 or CREBBP enhances apoptosis upon TRAIL stimulation in non-small-cell lung cancer (NSCLC) cells. A485 upregulates pro- and anti-apoptotic genes at the mRNA level, implying an apoptosis-modulating effect in NSCLC cells. However, A485 alone does not induce apoptosis. Interestingly, we observed that the number of apoptotic cells increases upon combined treatment with A485 and TRAIL. Therefore, A485, as a TRAIL-sensitizer, was used in combination with TRAIL in wild type of NSCLC cell lines (HCC827 and H1650) and cells with acquired erlotinib resistance (HCC827-ER and H1650-ER). Our results show that the combination of A485 and TRAIL synergistically increases cell death and inhibits long-term cell proliferation. Furthermore, this combination inhibits the growth of 3D spheroids of EGFR-TKI-resistant cells. Taken together, we demonstrate a successful combination of A485 and TRAIL in EGFR-TKI-sensitive and resistant NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Inibidores Enzimáticos/administração & dosagem , Histona Acetiltransferases/antagonistas & inibidores , Neoplasias Pulmonares/enzimologia , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Histona Acetiltransferases/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
17.
Pak J Pharm Sci ; 33(1(Special)): 499-504, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32173649

RESUMO

The purpose was to investigate the efficacy and safety of Osimertinib in the treatment of advanced non-small cell lung cancer and to analyze its effects on the expression of serum matrix metalloproteinase-7 (MMP-7) and matrix metallo-proteinase-9 (MMP-9). Eighty patients were equally divided into observation and control group. The observation group was given Osimertinib combined with conventional chemotherapy and the other was treated with conventional chemotherapy alone. The short-term efficacy, the levels of serum MMP-7, MMP-9 and adverse reactions were compared. The effectiveness and clinical benefit rate of the observation group were 62.50% and 92.50% respectively, significantly higher than the control group. There was no significant difference in MMP-7 and MMP-9 before treatment however there was a significant difference after treatment, and the serum MMP-7 & MMP-9 levels showed a trend of increasing with decreasing efficacy. After treatment, comparing with control group, serum MMP-7 and MMP-9 levels were significantly lower, the Karnofsky score was significantly higher, and the improvement effect of the quality of life was statistically significant. Besides, the incidence of leukopenia, thrombocytopenia, anemia and gastrointestinal symptoms were significantly lower. In the treatment of patients with advanced non-small cell lung cancer, Osimertinib significantly reduced the expression of serum MMP-7, MMP-9, improved the clinical benefit and quality of life of patients. The clinical efficacy was significant with a high safety.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinase 7 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Acrilamidas/efeitos adversos , Idoso , Compostos de Anilina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/psicologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
18.
Biochemistry ; 59(14): 1428-1441, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32207968

RESUMO

Osimertinib is a covalent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for treating non-small cell lung cancer patients with activating EGFR mutations (Exon19del or L858R) or with the T790M resistance mutation following disease progression on first- or second-generation EGFR TKIs. The aim of this work is to rationalize and understand how osimertinib achieves mutant EGFR selectivity over the wild-type (WT) by evaluating its kinetic mechanism of action. In doing so, we developed methodologies combining steady-state and pre-steady-state kinetics to determine the covalent inactivation rates (kinact) and reversible binding affinities (Ki) for osimertinib against WT, L858R, and L858R/T790M EGFR and compared these data to the inhibition kinetics of earlier generations of EGFR TKIs. The kinact/KI values indicate osimertinib inactivates L858R and L858R/T790M with 20- and 50-fold higher overall efficiencies, respectively, compared to that for WT. The Ki and kinact values reveal that osimertinib binds 3-fold tighter to and reacts 3-fold faster with L858R than WT EGFR and binds 17-fold tighter to and reacts 3-fold faster with L858R/T790M than with the WT EGFR. We conclude that osimertinib overcomes the T790M mutation through improved affinities from stronger hydrophobic interactions with Met790 versus Thr790 and an improved rate of covalent bond formation via better positioning of the acrylamide warhead, while osimertinib targets the L858R mutation through better affinities and reactivities with the mutant in the context of differential binding affinities of the competing substrate ATP. This work highlights the importance of optimizing both reversible drug-target interactions and inactivation rates for covalent inhibitors to achieve selectivity in targeting mutant EGFRs.


Assuntos
Acrilamidas/química , Compostos de Anilina/química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Inibidores de Proteínas Quinases/química , Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Cinética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/administração & dosagem
19.
Nat Cell Biol ; 22(4): 412-424, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203415

RESUMO

Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2 (ULK1/2) through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and the formation of autophagosome complexes. Increased levels of intracellular Cu are associated with starvation-induced autophagy and are sufficient to enhance ULK1 kinase activity and, in turn, autophagic flux. The growth and survival of lung tumours driven by KRASG12D is diminished in the absence of Ctr1, is dependent on ULK1 Cu binding and is associated with reduced levels of autophagy and signalling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to prevent autophagy signalling to limit proliferation and improve patient survival in cancer.


Assuntos
Adenocarcinoma de Pulmão/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Autofagia/genética , Cobre/metabolismo , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Proteínas Serina-Treonina Quinases/genética , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/patologia , Sequência de Aminoácidos , Animais , Autofagossomos/enzimologia , Proteína 5 Relacionada à Autofagia/deficiência , Proteína 5 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Transportador de Cobre 1/deficiência , Transportador de Cobre 1/genética , Fibroblastos/enzimologia , Fibroblastos/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/deficiência , Proteínas Proto-Oncogênicas p21(ras)/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Ecotoxicol Environ Saf ; 195: 110464, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171946

RESUMO

Nickel compounds are known to be common environmental and occupational carcinogens which also promote the migration of lung cancer cells. However, the molecular mechanism yet remains to be clarified. Hydrogen sulfide (H2S) is involved in cancer biological processes. However, the exact effect and functionality of H2S on nickel, towards the promotion of the migration ability of lung cancer cells, remains to be unknown. In this study, we have found that the nickel chloride (NiCl2) treatment significantly downregulates the protein levels of endogenous H2S enzyme cystathionine ß-synthase (CBS), cystathionine γ-lyase (CSE) and 3-Mercaptopyruvate sulfurtransferase (3-MST). A correlation between NiCl2-induced epithelial-mesenchymal transition (EMT) and the migration ability of lung cancer A549 cells has been observed. Exogenous H2S donor, sodium hydrogen sulfide (NaHS) (100 µmol/L), can reverse NiCl2-induced EMT as well as the migration ability of A549 cells. NiCl2 treatment is able to upregulate the protein level of transforming growth factor-ß1 (TGF-ß1), p-Smad2, p-Smad3, p-JNK, p-ERK and p-P38 in a time-dependent fashion, indicating that both TGF-ß1/Smad2/Smad3 and mitogen-activated protein kinase (MAPK) signaling cascades (a non-Smad pathway) may play essential roles in NiCl2-dependent EMT as well as cell migration of human lung cancer cells. Furthermore, exogenous NaHS alleviates the NiCl2-induced EMT and the migration ability of A549 cells only by regulating TGF-ß1/Smad2/Smad3, rather than the MAPK, signaling pathway. These results indicate that the exogenous administration of NaHS might be a potential therapeutic strategy against nickel-induced lung cancer progression.


Assuntos
Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Níquel/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia , Células A549 , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Humanos , Sulfeto de Hidrogênio/química , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Sulfurtransferases/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
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