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1.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166875, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37673358

RESUMO

Nicotinic acetylcholine receptors (nAChRs) have long been considered to solely mediate neurotransmission. However, their widespread distribution in the human body suggests a more diverse physiological role. Additionally, the expression of nAChRs is increased in certain cancers, such as lung cancer, and has been associated with cell proliferation, epithelial-to-mesenchymal cell transition, angiogenesis and apoptosis prevention. Several compounds that interact with these receptors have been identified as potential therapeutic agents. They have been tested as drugs for treating nicotine addiction, alcoholism, depression, pain and Alzheimer's disease. This review focuses on nAChR-mediated signalling in cancer, presenting opportunities for the development of innovative nAChR-based anticancer drugs. It displays the differences in expression of each nAChR subunit between normal and cancer cells for selected cancer types, highlighting their possible involvement in specific cases. Antagonists of nAChRs that could complement existing cancer therapies are summarised and critically discussed. We hope that this review will stimulate further research on the role of nAChRs in cancer potentially leading to innovative cancer therapies.


Assuntos
Neoplasias Pulmonares , Receptores Nicotínicos , Humanos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Nicotina , Neoplasias Pulmonares/metabolismo , Transdução de Sinais , Proliferação de Células
2.
J Ethnopharmacol ; 319(Pt 2): 117270, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37832810

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Huaier (Trametes robiniophila Murr), a traditional Chinese medicinal fungus, possesses potent anticancer efficacy and has been used as an adjuvant medication for liver, breast, gastric, intestinal, and non-small cell lung cancer (NSCLC). However, the potential regulatory functions and underlying molecular mechanisms of Huaier in cisplatin resistance of NSCLC remain unknown. AIM: To evaluate the potential regulatory functions and underlying molecular mechanisms of Huaier in cisplatin resistance of NSCLC. MATERIALS AND METHODS: In vitro and in vivo experiments were employed to evaluate the regulatory functions of Huaier in cisplatin-resistant NSCLC cells. Transcriptome sequencing and validation analyses was undertaken to identify the downstream targets of Huaier. Network pharmacology, ultra-performance liquid chromatography-mass spectroscopy, and in vitro and in vivo experiments were performed to identify key small molecule drug candidates in Huaier and the regulatory mechanisms these employ to suppress cisplatin resistance in NSCLC. RESULTS: Huaier suppressed cisplatin resistance and cancer cell stemness in cisplatin-resistant NSCLC cells, both in vitro and in vivo. Mechanistically, Huaier could suppress expression of interleuken-8 (IL-8) through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein-1 (AP-1), two key transcription factors responsible for the activation of IL-8 transcription. Kaempferol was identified as one of the key small molecule compounds in Huaier that could suppress cisplatin resistance by inhibiting the phosphorylation and nuclear translocation of proto-oncogene c-Jun (JUN) by binding and inhibiting the kinase activity of c-Jun N-terminal protein kinase (JNK). CONCLUSIONS: Huaier suppressed cisplatin resistance of NSCLC cells by inhibiting the JNK/JUN/IL-8 signaling pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Trametes/química , Trametes/metabolismo , Fator de Transcrição AP-1/metabolismo , Interleucina-8 , Transdução de Sinais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral
3.
Biochim Biophys Acta Mol Cell Res ; 1871(1): 119588, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37739270

RESUMO

Protein phosphatase 4 (PP4) plays an indispensable regulatory part in the development and malignant progression of multifarious tumors. Nevertheless, the function of protein phosphatase 4 regulatory subunit 1 (PP4R1), a vital regulatory subunit of PP4, in tumors especially in lung cancer remains blurred. Therefore, this study aimed to investigate the function and mechanism of PP4R1 in the development of non-small cell lung cancer (NSCLC). We analyzed the clinical correlation of PP4R1 based on the TCGA database by UALCAN (https://ualcan.path.uab.edu/index.html) and found that hyper-expression of PP4R1 mRNA was related to the severe prognosis in NSCLC. The subsequent cellular experiments confirmed that the proliferation, colony growth, migration as well as invasion of H1299 and HCC827 were significantly enhanced after PP4R1 overexpression treatment in vitro. Results from animal experiments pointed out that tumors exhibited stronger growth and lung metastatic capacities due to the overexpression of PP4R1. The bioinformatics analysis, including RNA-seq, showed us that PP4R1 significantly promoted the expression of several HSP70 family member genes, with a particularly marked increase in HSPA6, and the enrichment analyses illustrated that the differentially expressed genes (DEGs) were enriched in those pathways related to protein folding. More importantly, the overexpression of HSPA6 resulted in the same malignant progression of NSCLC as PP4R1 overexpression, and both concomitant with the activation of endoplasmic reticulum (ER) stress. In aggregate, PP4R1 contributed to the malignant progression of NSCLC via up-regulating HSPA6 expression and then activating ER stress.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/metabolismo , Estresse do Retículo Endoplasmático/genética
4.
Gene ; 893: 147954, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37923092

RESUMO

lncRNA Prader Willi/Angelman Region RNA 6 (PWAR6) is considered to play a protective lncRNA in glioma, but, the role of PWAR6 in the occurrence and cisplatin resistance of non-small cell lung cancer (NSCLC) is elusive. In the study, we aimed to assess the role of PWAR6 in the cisplatin resistance of NSCLC. Based on the oebiotech and TargetScanHuman database, we predicted the interaction between PWAR6, miR-577 and PHACTR1. We then used small interfering RNA (siRNA), miRNA mimics and dual-luciferase reporter assay to explore the regulatory role of PWAR6/miR-577PHACTR1. Based on the online database, miR-577 can interact with PWAR6 and PHACTR1. Soon afterwards, we observed that the expression of PWAR6 and PHACTR1 was increased, while miR-577 expression was decreased in A549/DDP cells. And the cell viability was decreased, while cell apoptosis was increased in A549/DDP cells. What's more, PWAR6 knockdown can promote the expression of miR-577 and inhibit the expression of PHACTR1. PWAR6 knockdown elevated cell proliferation and reduced cell apoptosis of A549/DDP cells. Interestingly, we found that miR-577 can interact with PHACTR1 to regulate the proliferation and apoptosis of A549/DDP cells. To conclude, we speculated that PWAR6 knockdown elevated cell proliferation and reduced cell apoptosis of A549/DDP cells via miR-577/PHACTR1, providing the theoretical basis for the clinical treatment of NSCLC patients.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , RNA Longo não Codificante/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/metabolismo , RNA Interferente Pequeno/uso terapêutico , Proliferação de Células , Linhagem Celular Tumoral
5.
J Pharm Biomed Anal ; 238: 115803, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-37871417

RESUMO

The blood proteome, consisting of thousands of proteins engaged in various biological processes, acts as a valuable source of potential biomarkers for various medical applications. PROphet is a plasma proteomics-based test that serves as a decision-support tool for non-small cell lung cancer (NSCLC) patients, combining proteomic profiling using SomaScan technology and subsequent computational algorithm. PROphet was implemented as a laboratory developed test (LDT). Under the Clinical Laboratory Improvement Amendments (CLIA) and Commission on Office Laboratory Accreditation (COLA) regulations, prior to releasing patient test results, a clinical laboratory located in the United States employing an LDT must examine its performance characteristics with regard to analytical validity. This study describes the experimental and computational analytical validity of the PROphet test, as required by CLIA/COLA regulations. Experimental precision analysis displayed a median coefficient of variation (CV) of 3.9 % and 4.7 % for intra-plate and inter-plate examination, respectively, and the median accuracy rate between sites was 88 %. Computational precision exhibited a high accuracy rate, with 93 % of samples displaying complete concordance in results. A cross-platform comparison between SomaScan and other proteomics platforms yielded a median Spearman's rank correlation coefficient of 0.51, affirming the consistency and reliability of the SomaScan platform as used under the PROphet test. Our study presents a robust framework for evaluating the analytical validity of a platform that combines an experimental assay with subsequent computational algorithms. When applied to the PROphet test, strong analytical performance of the test was demonstrated.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Estados Unidos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteômica/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Reprodutibilidade dos Testes , Biomarcadores/metabolismo
6.
Curr Mol Pharmacol ; 17: e210723218988, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37489792

RESUMO

BACKGROUND: Lung cancer is a leading cause of cancer mortality. It is one of the most abundant cancer types clinically, with 2 million new cases diagnosed yearly. AIMS: Using clinically collected non-small cell lung cancer (NSCLC) samples, we sought to hypothesize an innovative intact signaling cascade for the disorder. METHODS: We dissected snap-frozen NSCLC tissues along with sibling-paired nearby non-tumorous tissues from 108 NSCLC patients. We measured the expression levels of miR-451/ETV4/MMP13 using qRT-PCR and did a thorough investigation of the molecular mechanism for the signaling axis in NSCLC cell line A549. We also studied the epithelial-mesenchymal transition (EMT) process. RESULTS: The activity of miR-451 was significantly decreased in NSCLC tissues, while the expression levels of ETV4 and MMP13 were remarkably increased. At the same time, miR-451 levels maintained a declining trend across TNM stage I-III. Inversely, ETV4 and MMP13 increased as the TNM stage increased. The miR-451/ETV4/MMP13 signaling axis was closely associated with prognosis in NSCLC patients. Based on in vitro experiments, ETV4 was a direct targeting factor for miRNA-451. Meanwhile, ETV4 promoted the tumor properties of NSCLC cells by directly activating MMP13. Silencing MMP13 blocked the EMT progress of NSCLC cells. CONCLUSION: Overall, we hypothesized an impeccable signaling pathway for NSCLC from a new aspect, and this can offer alternative insights for a better understanding of the disorder.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Metaloproteinase 13 da Matriz , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Transdução de Sinais
7.
Cell Signal ; 113: 110962, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37931691

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is a prevalent and aggressive malignancy with limited therapeutic options. Despite advances in treatment, NSCLC remains a major cause of cancer-related death worldwide. Tumor heterogeneity and therapy resistance present challenges in achieving remission. Research is needed to provide molecular insights, identify new targets, and develop personalized therapies to improve outcomes. METHODS: The protein expression level and prognostic value of DHX38 in NSCLC were explored in public databases and NSCLC tissue microarrays. DHX38 knockdown and overexpression cell lines were established to evaluate the role of DHX38 in NSCLC. In vitro and in vivo functional experiments were conducted to assess proliferation and metastasis. To determine the underlying molecular mechanism of DHX38 in human NSCLC, proteins that interact with DHX38 were isolated by IP and identified by LC-MS. KEGG analysis of DHX38-interacting proteins revealed the molecular pathway of DHX38 in human NSCLC. Abnormal pathway activation was verified by Western blot analysis and immunohistochemical (IHC) staining. A molecule-specific inhibitor was further used to explore potential therapeutic targets for NSCLC. The pathway-related target that interacted with DHX38 was verified by co-immunoprecipitation(co-IP) experiments. In cell lines with stable DHX38 overexpression, the target protein was knocked down to explore its complementary effect on DHX38 overexpression-induced tumor promotion. RESULTS: The protein expression of DHX38 was increased in NSCLC, and patients with high DHX38 expression levels had a poor prognosis. In vitro and in vivo experiments showed that DHX38 promoted the proliferation, migration and invasion of human NSCLC cells. DHX38 overexpression caused abnormal activation of the MAPK pathway and promoted epithelial-mesenchymal transition (EMT) in tumours. SCH772984, a novel specific ERK1/2 inhibitor, significantly reduced the increases in cell proliferation, migration and invasion caused by DHX38 overexpression. The co-IP experiments confirmed that DHX38 interacted with the Ras GTPase-activating protein-binding protein G3BP1. DHX38 regulated the expression of G3BP1. Knocking down G3BP1 in cells with stable DHX38 overexpression prevented DHX38-induced tumor cell proliferation, migration and invasion. Silencing G3BP1 reversed the MAPK pathway activation and EMT induced by DHX38 overexpression. CONCLUSION: In NSCLC, DHX38 functions as a tumor promoter. DHX38 modulates G3BP1 expression, leading to the activation of the MAPK signaling pathway, thus promoting tumor cell proliferation, metastasis, and the progression of epithelial-mesenchymal transition (EMT) in non-small cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , DNA Helicases/metabolismo , Transição Epitelial-Mesenquimal , Linhagem Celular Tumoral , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , RNA Helicases/metabolismo , Proliferação de Células , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Fatores de Processamento de RNA/metabolismo , RNA Helicases DEAD-box/metabolismo
8.
Redox Rep ; 28(1): 2284517, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38041592

RESUMO

Melittin, a naturally occurring polypeptide found in bee venom, has been recognized for its potential anti-tumor effects, particularly in the context of lung cancer. Our previous study focused on its impact on human lung adenocarcinoma cells A549, revealing that melittin induces intracellular reactive oxygen species (ROS) burst and oxidative damage, resulting in cell death. Considering the significant role of mitochondria in maintaining intracellular redox levels and ROS, we further examined the involvement of mitochondrial damage in melittin-induced apoptosis in lung cancer cells. Our findings demonstrated that melittin caused changes in mitochondrial membrane potential (MMP), triggered mitochondrial ROS burst (Figure 1), and activated the mitochondria-related apoptosis pathway Bax/Bcl-2 by directly targeting mitochondria in A549 cells (Figure 2). Further, we infected A549 cells using a lentivirus that can express melittin-Myc and confirmed that melittin can directly target binding to mitochondria, causing the biological effects described above (Figure 2). Notably, melittin induced mitochondrial damage while inhibiting autophagy, resulting in abnormal degradation of damaged mitochondria (Figure 5). To summarize, our study unveils that melittin targets mitochondria, causing mitochondrial damage, and inhibits the autophagy-lysosomal degradation pathway. This process triggers mitoROS burst and ultimately activates the mitochondria-associated Bax/Bcl-2 apoptotic signaling pathways in A549 cells.


Assuntos
Neoplasias Pulmonares , Mitofagia , Humanos , Células A549 , Meliteno/farmacologia , Meliteno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia , Mitocôndrias/metabolismo , Apoptose , Potencial da Membrana Mitocondrial , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo
9.
BMC Complement Med Ther ; 23(1): 436, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-38049779

RESUMO

BACKGROUND: Despite the critical progress of non-small cell lung cancer (NSCLC) therapeutic approaches, the clinical outcomes remain considerably poor. The requirement of developing novel therapeutic interventions is still urgent. In this study, we showed for the first time that diosbulbin C, a natural diterpene lactone component extracted from traditional Chinese medicine Dioscorea bulbifera L., possesses high anticancer activity in NSCLC. METHODS: A549 and NCI-H1299 cells were used. The inhibitory effects of the diosbulbin C on NSCLC cell proliferation were evaluated using cytotoxicity, clone formation, EdU assay, and flow cytometry. Network pharmacology methods were used to explore the targets through which the diosbulbin C inhibited NSCLC cell proliferation. Molecular docking, qRT-PCR, and western blotting were used to validate the molecular targets and regulated molecules of diosbulbin C in NSCLC. RESULTS: Diosbulbin C treatment in NSCLC cells results in a remarkable reduction in cell proliferation and induces significant G0/G1 phase cell cycle arrest. AKT1, DHFR, and TYMS were identified as the potential targets of diosbulbin C. Diosbulbin C may inhibit NSCLC cell proliferation by downregulating the expression/activation of AKT, DHFR, and TYMS. In addition, diosbulbin C was predicted to exhibit high drug-likeness properties with good water solubility and intestinal absorption, highlighting its potential value in the discovery and development of anti-lung cancer drugs. CONCLUSIONS: Diosbulbin C induces cell cycle arrest and inhibits the proliferation of NSCLC cells, possibly by downregulating the expression/activation of AKT, DHFR, and TYMS.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Dioscorea , Neoplasias Pulmonares , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simulação de Acoplamento Molecular , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Fase G1
10.
J Exp Clin Cancer Res ; 42(1): 330, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38049814

RESUMO

BACKGROUND: CircRNA is recognized for its significant regulatory function across various cancers. However, its regulatory role in non-small cell lung cancer (NSCLC) is still largely uncharted. METHODS: Analysis based on public databases is completed using R software. circATP9A was identified by two circRNA datasets of NSCLC from the Gene Expression Omnibus database. To examine the impact of circATP9A on the phenotype of NSCLC, we conducted both in vitro and in vivo functional experiments. The mRNA and protein levels of specific molecules were determined through quantitative real-time PCR and western blot assays. RNA pulldown and RNA immunoprecipitation assays were performed to verify the interaction between RNA and protein. The functional role of extracellular vesicles (EVs)-circATP9A on tumor-associated macrophage (TAM) polarization was assessed using co-culture system and cell flow cytometry. RESULTS: Here, we elucidates the functional role of circATP9A in NSCLC. We demonstrated that circATP9A can foster the progression of NSCLC through in vivo and in vitro experiments. From a mechanistic standpoint, circATP9A can interact with the HuR protein to form an RNA-protein complex, subsequently amplifying the mRNA and protein levels of the target gene NUCKS1. Further, the PI3K/AKT/mTOR signaling was identified as the downstream pathways of circATP9A/HuR/NUCKS1 axis. More notably, hnRNPA2B1 can mediate the incorporation of circATP9A into EVs. Subsequently, these EVs containing circATP9A induce the M2 phenotype of TAMs, thereby facilitating NSCLC development. CONCLUSIONS: Our discoveries indicate that circATP9A could serve as a promising diagnostic indicator and a therapeutic target for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Vesículas Extracelulares , Neoplasias Pulmonares , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , RNA/metabolismo , Macrófagos/metabolismo , RNA Mensageiro/metabolismo , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , MicroRNAs/genética
11.
J Clin Invest ; 133(21)2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37909331

RESUMO

Although subsets of patients with lung squamous cell carcinoma (LSCC) benefit from immunotherapy, there are few effective molecularly targeted treatments for LSCC. Fibroblast growth factor receptor (FGFR) inhibitors provide a therapeutic option for patients with LSCC harboring FGFR aberrations, but their therapeutic efficacy has been limited to date. In this issue of the JCI, Malchers et al. identified tail-to-tail rearrangements, either within or near FGFR1, that are associated with FGFR1 dependency and sensitivity to FGFR inhibition in LSCC. These results may help improve the selection of patients with LSCC who are most likely to benefit from treatment with FGFR inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Genômica , Células Epiteliais/metabolismo
12.
Int J Mol Sci ; 24(21)2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37958764

RESUMO

Multicellular tumor spheroids are a good tool for testing new anticancer drugs, including those that may target cancer stem cells (CSCs), which are responsible for cancer progression, metastasis, and recurrence. Therefore, we applied this model in our studies of highly active antitumor unsymmetrical bisacridines (UAs). We investigated the cellular response induced by UAs in 2D and 3D cultures of HCT116 colon and A549 lung cancer cells, with an additional focus on their impact on the CSC-like population. We showed that UAs affected the viability of the studied cells, as well as their spherogenic potential in the 2D and 3D cultures. Furthermore, we proved that the most promising UAs (C-2045 and C-2053) induced apoptosis in the HCT116 and A549 spheres to a similar, or even higher, extent than what was found in monolayer conditions. Next, we identified the population of the CSC-like cells in the 2D and 3D cultures of the studied cell lines by determining the levels of CD166, CD133, CD44, and EpCAM markers. We showed that the selected UAs affected the CSC-like population in both of the cell lines, and that A549 was affected more profoundly in 3D than in 2D cultures. Thus, the UAs exhibited high antitumor properties in both the 2D and 3D conditions, which makes them promising candidates for future therapeutic applications.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/metabolismo , Esferoides Celulares , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Células Tumorais Cultivadas , Células-Tronco Neoplásicas/metabolismo , Colo , Linhagem Celular Tumoral
13.
Molecules ; 28(21)2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37959865

RESUMO

Lung cancer has a high incidence rate worldwide, necessitating the development of new drugs. Although Magnolia figo (Lour.) DC. is known for its medicinal properties, studies on its efficacy against lung cancer are lacking. This study investigated whether the supercritical fluid extract of M. figo (FMO) can induce apoptosis in A549, a human non-small-cell lung cancer cell line. The cell viability was assessed using an MTT assay. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis and flow cytometry analysis were conducted. The expression of factors was assessed through Western blotting analyses. Gas chromatography-mass spectrometry (GC-MS) was performed. The results revealed that FMO treatment exhibited cytotoxicity, demonstrating dose-dependent effects. The TUNEL analysis and flow cytometry analysis revealed that FMO induced apoptosis in A549 cells. The Western blotting analysis revealed that FMO upregulated the expression of p53 and Bax protein, and downregulated the expression of Bcl-2 protein. The GC-MS analysis revealed eight components identified in FMO. These findings indicate that FMO can induce A549 apoptosis through the p53/Bcl-2/Bax pathways, confirming the apoptotic effects of M. figo on lung cancer cells. These results highlight the potential, for the first time, of M. figo as a source for developing novel drugs for lung cancer treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Magnolia , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Magnolia/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proliferação de Células
14.
Medicine (Baltimore) ; 102(45): e35837, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37960731

RESUMO

Splicing factor proline- and glutamine-rich (SFPQ) can interact with RNAs to regulate gene expression. The function of SFPQ in the immunotherapy of non-small cell lung cancer (NSCLC) is investigated in this study. H1299 and A549 cells were transfected with shSFPQ plasmid. Cell counting kit-8 (CCK-8) and cell clone formation were utilized to detect survival and proliferation. Programmed death-ligand 1 (PD-L1) and SFPQ were detected in NSCLC patients treated with anti-PD-L1 antibody. Dual-luciferase assays, RNA immunoblotting, RNA pull-down, and mRNA stability assay were applied to verify the regulation of PD-L1 with SFPQ. Human peripheral blood mononuclear cells (PBMC)-derived dendritic cells were loaded with irradiated A549 and H1299 cells, which were cultured with autologous CD8+T cells and tumor cells to perform in vitro tumor-specific cytotoxic T lymphocytes (CTL) cytotoxicity analysis. SFPQ silencing inhibited the survival and proliferation of H1299 and A549 cells with down-regulated PD-L1 expression. PD-L1 and SFPQ expression were markedly higher in anti-PD-L1 antibody treatment responders compared to non-responders, which showed a positive Pearson correlation (R = 0.76, P < .001). SFPQ up-regulated the relative mRNA and protein expression of PD-L1 by binding to the PD-L1 3'UTR to slow the decay of PD-L1 mRNA. SFPQ silencing promoted the killing effect of CTL on A549 and H1299 cells. SFPQ up-regulates PD-L1 expression by binding with PD-L1 3'UTR to slow the decay of PD-L1 mRNA, and SFPQ silencing promotes CTL-mediated cytotoxicity on NSCLC cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Regiões 3' não Traduzidas , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Glutamina , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Fatores de Processamento de RNA/genética , Linfócitos T Citotóxicos/metabolismo , Fator de Processamento Associado a PTB/genética , Fator de Processamento Associado a PTB/metabolismo
15.
Respir Res ; 24(1): 279, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37964265

RESUMO

BACKGROUND: Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking. METHODS: Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated. RESULTS: We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics. CONCLUSIONS: Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.


Assuntos
Fibrose Pulmonar Idiopática , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Receptor de Morte Celular Programada 1/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Pulmão/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Bleomicina/toxicidade , Neoplasias Pulmonares/metabolismo , Linfonodos/patologia , RNA Mensageiro/genética
16.
Biomed Pharmacother ; 168: 115798, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37913733

RESUMO

Despite extensive efforts and ongoing progress in personalized anticancer approaches, chemotherapy remains the first line or the only treatment for some tumors that may develop resistance to chemotherapeutics in time due to inter alia overexpression of ATP-binding cassette transporters. Using clinically-relevant resistant models of triple negative breast cancer (MDA-MB-231; TNBC) as well as non-small cell lung cancer (A549; NSCLC), we tested the efficacy of I-CBP112 - CBP/EP300 bromodomain inhibitor to overcome drug resistance by declining ABC gene transcription. I-CBP112 significantly reduced ABCB1, ABCC1, ABCC2, ABCC3, ABCC5 and ABCG2 in all resistant lines, as well as ABCC10 in TNBC and ABCC4 in paclitaxel-resistant NSCLC, thereby increasing intracellular drug accumulation and cytotoxicity in 2D and 3D cultures. This was phenocopied only by the joint effect of ABC inhibitors such as tariquidar (ABCB1 - P-glycoprotein and ABCG2) and MK-571 (ABCC), whereas single inhibition of ABCB1/ABCG2 or ABCC proteins did not affect drug accumulation, thereby implying the need of simultaneous deficiency in activity of majority of drug pumps for enhanced drug retention. I-CBP112 failed to directly inhibit activity of ABCB1, ABCG2 and ABCC subfamily members at the same time. Importantly, I-CBP112 treated cancer cells polarized human macrophages into proinflammatory phenotypes. Moreover, I-CBP112 remained non-toxic to primary cell lines, nor did it enhance anticancer drug toxicity to blood-immune cells. In silico assay of ADMET properties confirmed the desired pharmacokinetic features of I-CBP112. The results suggest that the CBP/p300 inhibitor is a promising co-adjuvant to chemotherapy in drug-resistant cancer phenotypes, capable of decreasing ABC transporter expression.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Humanos , Transportadores de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células A549 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico
17.
Biomed Pharmacother ; 168: 115789, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37924787

RESUMO

Lung cancer is the most commonly diagnosed cancer and the one that causes the most deaths worldwide, so there is a need for therapies that improve survival rates. Products derived from marine organisms are a source of novel and potent antitumor compounds, but they present the great obstacle of their obtaining from the natural environment and the problems associated with the synthesis and biological effects of chemical analogues. In this work, a Bengamide analogue (Bengamide II) was chemically synthesized and in vitro and in vivo studies were performed to determine its antitumor activity and mechanisms of action. It was shown to have potent antiproliferative activity in lung cancer lines in 2D and 3D models. In addition, Bengamide II-treated cells showed G2/M and G0/G1 cell cycle arrest, together with a decrease in the proliferation marker Ki67. As for the mechanism of action, the treatment was associated with increased LC3-II expression and production of acidic vesicles signaling autophagy. In addition, Bengamide II treatment was associated with caspase-3 activation and DNA fragmentation related to apoptosis. Furthermore, a reduction of VEGFA expression, related to angiogenesis, was also observed. In vivo studies showed that Bengamide II markedly reduced tumor volume and metastases increasing survival. Additionally, it revealed no systemic toxicity in in vivo models at the therapeutic doses used, which is essential for its future clinical use. Taken together, the chemically synthesized bengamide analogue Bengamide II, is a promising drug for lung cancer treatment showing relevant antitumor activity and significant safety.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células , Linhagem Celular Tumoral , Transdução de Sinais , Apoptose
18.
Biomed Pharmacother ; 168: 115826, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37931514

RESUMO

Stimulus-responsive nanodrugs have been extensively studied and their structural changes in the cells are important for controlled intracellular drug release. Histone citrullination of peptidylarginine deiminase 4 (PAD4) regulates the expression of tumor suppressor genes. In our previous study, compounds such as YW3-56 (356) were developed as potent PAD4 inhibitors with excellent anti-tumor activity in vitro and in vivo. To enhance the antitumor activity and improve the bioavailability, we further optimized the structure by modifying the phenylboronic acid moiety to the PAD4 inhibitor (4B). Taking advantage of the oxidative stress responsiveness of the phenylboronic acid moiety, in this study, we covalently attached 4B to RGD sequence peptide modified chitosan (K-CRGDV) to construct this new oxidative stress responsive nanodrug (K-CRGDV-4B). The modification of RGD sequence peptide conferred the nanodrug the ability to actively target tumors. The release mechanism was verified by UV-Vis spectroscopy, NMR. The anti-tumor and anti-metastatic properties of K-CRGDV-4B were demonstrated by in vitro cytotoxicity assay and in vivo mouse Lewis lung cancer metastasis model. In addition, K-CRGDV-4B modulates the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins such as PD1 were inhibited, while IFN-γ and IFN-ß, which are stimulators of tumor immune responses, were upregulated. Overall, K-CRGDV-4B is a stimulus-responsive nanodrug that responds to the tumor microenvironment by inhibiting PAD4 activity, blocking the formation of neutrophil extracellular traps (NETs), and improving the tumor immune microenvironment.


Assuntos
Quitosana , Neoplasias Pulmonares , Camundongos , Animais , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Nanomedicina , Oligopeptídeos/farmacologia , Oligopeptídeos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neutrófilos/metabolismo , Microambiente Tumoral
19.
Int J Med Sci ; 20(13): 1662-1670, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37928877

RESUMO

Lung cancer is one of the most frequently diagnosed cancers worldwide. Due to its late diagnosis, it remains the leading cause of cancer-related deaths. Despite it is mostly associated to tobacco smoking, recent data suggested that genetic factors are of the highest importance. In this context, different processes meaningful for the development and progression of lung cancer such endocytosis, protein secretion and signal transduction, are controlled by membrane rafts. These highly ordered membrane domains contain proteins such as caveolins and flotillins, which were traditionally considered scaffold proteins but have currently been given a preponderant role in lung cancer. Here, we summarize current knowledge regarding the involvement of caveolins and flotillins in lung cancer from a molecular point of view.


Assuntos
Caveolinas , Neoplasias Pulmonares , Humanos , Caveolinas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microdomínios da Membrana
20.
Front Immunol ; 14: 1279495, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37915578

RESUMO

The immune system plays a critical role in cancer, including lung cancer, which is the leading cause of cancer-related deaths worldwide. Immunotherapy, particularly immune checkpoint blockade, has revolutionized the treatment of lung cancer, but a large subset of patients either do not respond or develop resistance. Exosomes, essential mediators of cell-to-cell communication, exert a profound influence on the tumor microenvironment and the interplay between cancer and the immune system. This review focuses on the role of tumor-derived exosomes and immune cells-derived exosomes in the crosstalk between these cell types, influencing the initiation and progression of lung cancer. Depending on their cell of origin and microenvironment, exosomes can contain immunosuppressive or immunostimulatory molecules that can either promote or inhibit tumor growth, thus playing a dual role in the disease. Furthermore, the use of exosomes in lung cancer immunotherapy is discussed. Their potential applications as cell-free vaccines and drug delivery systems make them an attractive option for lung cancer treatment. Additionally, exosomal proteins and RNAs emerge as promising biomarkers that could be employed for the prediction, diagnosis, prognosis and monitoring of the disease. In summary, this review assesses the relationship between exosomes, lung cancer, and the immune system, shedding light on their potential clinical applications and future perspectives.


Assuntos
Exossomos , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Exossomos/metabolismo , Sistema Imunitário/metabolismo , Comunicação Celular , Imunoterapia , Microambiente Tumoral
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