EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 4.384
Fangyin Zhu,Liang Xu,Xudong Li,Ziying Li,Jun Wang,Haijun Chen,Xiumei Li,Yu Gao
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-based molecular targeted therapy are proved to be effective in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutation, its efficacy is limited by the acquired drug resistance. The combination of EGFR-TKIs with photodynamic therapy (PDT) has been explored to combat NSCLC with promising synergistic results. However, hypoxic tumor microenvironment is associated with the development of EGFR-TKIs resistance and severely limits the efficacy of PDT. Here, we synthesized an aptamer modified fluorinated dendrimer (APF) as a drug carrier and prepared nanocomplexes APFHG by encapsulation of gefitinib (Gef) and hematoporphyrin (Hp). APF has good oxygen-carrying capacity, high drug entrapment efficiency, and could release Gef and Hp in response to intracellular pH. APF can specifically recognize EGFR-positive NSCLC cells and effectively improve the tumor hypoxic microenvironment due to the targeting effect of aptamer and the good oxygen-carrying capacity of the fluorinated dendrimer. Under the laser irradiation, APFHG can significantly increase the production of the intracellular reactive oxygen species and produce a synergistic therapeutic effect in inhibition of cellular growth and induction of cell cycle arrest and apoptosis on both Gef-sensitive and Gef-resistant EGFR-mutant NSCLC cells through PDT/molecular targeted therapy. This work indicates that fluorinated dendrimer could be a potent drug delivery platform to overcome hypoxia-related resistance and the co-delivery of EGFR-TKI and photosensitizer by the fluorinated dendrimer could be a promising therapeutic approach for reversal of EGFR-TKIs resistance in EGFR mutation-positive NSCLC.
研究领域:
肿瘤学
·
药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2019
·
IF 8.355
Yingying Zhang,Lu Zhang,Xiaowen Lin,Lingjie Ke,Bifei Li,Liang Xu,Tingting Lv,Ziying Li,Haijun Chen,Yu Gao
The clinical outcome of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is limited by the ambiguous molecular subtypes of non-small cell lung cancer (NSCLC) patients and the emergence of drug-resistance. Here, a nanotheranostic agent ECMI, which is indocyanine green (ICG)-loaded mesoporous silica nanoparticles lidded with ZnO QDs and wrapped with erlotinib-modified chitosan, was developed for accurately determination of molecular subtypes and synergistic therapy. The erlotinib could guide ECMI into EGFR-mutated NSCLC cells and acquire a pH/redox dual-responsive release of ICG for precise fluorescent imaging. The ECMI could exert synergistic photodynamic/molecular targeted therapeutic effects under near-infrared irradiation in either erlotinib-sensitive or erlotinib-resistant EGFR-mutated NSCLC cells. In vivo experiments further showed that ECMI had distinct distribution behaviors in different NSCLC models and demonstrated synergistic anticancer effects. These results indicated that ECMI could be a promising nanotheranostic agent to treat EGFR-mutated NSCLC, and could provide a new perspective for individualized treatment.
研究领域:
肿瘤学
·
分子生物学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Yinlan Xu,Jie Dong,Hejun Liu,Jinmei Zheng,Haonan Guo,Yue Chen,Jialin Wang,Weidong Wu
Network pharmacology and docking identified key compounds and targets. • Osthole and matrine were key bioactives against lead-exposed NSCLC. • Core targets and pathways in lead-driven NSCLC were identified. • In vitro assays confirmed inhibition of NSCLC progression. Background Non-small cell lung cancer (NSCLC) is the predominant subtype of lung malignancy. Accumulating epidemiological evidence demonstrates that environmental lead (Pb) exposure as a critical driver of its initiation and progression. Purpose This study integrated network pharmacology, molecular docking, and in vitro assays to investigate the oncogenic effects of low-concentration Pb on A549 cells and explore the potential therapeutic mechanisms of osthole and matrine. Study design and methods Network pharmacology identified key potential signaling pathways, and molecular docking screened genes with higher binding affinity to the target. MTT assay was used to determine CC 50 , maximum safe concentration (MNTC) and cellular proliferative capacity of Pb, matrine and osthole. Scratch test and Matrigel invasion test detected A549 cell migration and invasion; flow cytometry detected apoptosis, ∆Ψm, ROS and cell cycle. qRT-PCR and Western blot measured gene expression levels. Results Network pharmacology analysis showed that the shared targets of osthole, Pb and NSCLC were mainly enriched in the PI3K/AKT and apoptosis pathways, while matrine, Pb, and NSCLC targets were primarily enriched in cancer metabolism, key hub genes included CDK2, CASP9, IKBKB, PDPK1 and MDM2. Molecular docking demonstrated that osthole showed strong binding to HSD11B1 and CDK2, while matrine exhibited high affinity for DRD4 and CDK2. Considering the essential functions of CDK2 in G1 phase transition, PDPK1, IKBKB, and CASP9 in cell survival, inflammatory signaling, and mitochondrial apoptosis, and MDM2 in p53-mediated cell cycle regulation, phenotypic validation experiments were conducted. Pb exposure significantly enhanced malignant characteristics of A549 cells, including increased migratory and invasive abilities, decreased apoptosis, and a significant reduction in mitochondrial membrane potential. At the molecular level, Pb exposure disrupted cellular homeostasis, as reflected by altered expression of SIRT-1, NRF-1, TGF-β1, Smad, STAT3, STAT1, and mtTFA. Treatment with osthole or matrine effectively reversed all lead-induced abnormalities. Conclusion Taken together, osthole or matrine exerts anti-cancer effects against Pb- promoted NSCLC progression by restoring disrupted cellular homeostasis through modulating cell cycle progression, inhibiting Pb-induced mitochondrial dysfunction and stress-related signaling imbalance. Download: Download high-res image (130KB) Download: Download full-size image
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Mengjie Wang,Xin Dai,Xu Yang,Baichuan Jin,Yueli Xie,Chenlu Xu,Qiqi liu,Lichao Wang,Lisha Ying,Weishan Lu,Qixun Chen,Ting Fu,Dan Su,Yuan Liu,Weihong Tan
Diagnosis of benign and malignant small nodules of the lung remains an unmet clinical problem which is leading to serious false positive diagnosis and overtreatment. Here, we developed a serum protein fishing-based spectral library (ProteoFish) for data independent acquisition analysis and a machine learning-boosted protein panel for diagnosis of early Non-Small Cell Lung Cancer (NSCLC) and classification of benign and malignant small nodules. We established an extensive NSCLC protein bank consisting of 297 clinical subjects. After testing 5 feature extraction algorithms and six machine learning models, the Lasso algorithm for a 15-key protein panel selection and Random Forest was chosen for diagnostic classification. Our random forest classifier achieved 91.38% accuracy in benign and malignant small nodule diagnosis, which is superior to the existing clinical assays. By integrating with machine learning, the 15-key protein panel may provide insights to multiplexed protein biomarker fishing from serum for facile cancer screening and tackling the current clinical challenge in prospective diagnostic classification of small nodules of the lung.
研究领域:
医学诊断
·
蛋白质组学
·
机器学习
·
癌症研究
·
临床生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Menglong Zhao,Danqing Wu,Weiqian Qiu,Hongchen Zhang,Min Chen,Haixia Zhou,Xiaoxia Ye,Zhong Han,Xiangchao Shi
4-anilinoquinazoline scaffold, a key structure in the development of EGFR-TKI anticancer drugs such as Gefitinib and Erlotinib, continues to drive advancements in non-small cell lung cancer (NSCLC) therapy. In this study, we synthesized a series of novel derivatives ( B3–B11 ). Structure-activity relationship (SAR) analysis revealed that electron-donating groups para-substituted at the 4-anilino position significantly enhanced antiproliferative activity. Notably, B10 incorporating an acrylamide group at the 4-anilino position demonstrated the most potent activity against NSCLC, with an IC 50 of 1.28 μM in A549 cells, nearly six times more effective than Gefitinib (7.81 μM). Acute toxicity studies confirmed that B10 is safe at doses below 50 mg/kg. In vivo studies using an A549 xenograft model showed a 46 % tumor growth inhibition (TGI) with B10 (25 mg/kg), surpassing the 21 % inhibition of Gefitinib at the same dose. Mechanistic studies revealed that B10 inhibited the AKT/GSK-3β/β-catenin signaling pathway, downregulating Wnt target genes (c-Myc, c-Jun), and reduced COX2 expression and IL-8 levels, showcasing its dual anti-inflammatory and antitumor effects. These results position B10 as a promising NSCLC therapeutic candidate, combining potent efficacy with a favorable safety profile, and enhance our understanding of the SAR and mechanism of action of 4-anilinoquinazoline derivatives.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
·
2023
·
IF 3.3
Peng-Cheng Zhong,Zhi-Wen Liu,Qi-Chang Xing,Jia Chen,Rui-Pei Yang
Non-small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer cases. Neferine is used as a traditional Chinese medicine with many pharmacological effects, including antitumor properties; however, it has not been reported whether neferine plays an anticancer role by causing pyroptosis in NSCLC cells. We used two typical lung cancer cell lines, A549 and H1299, and 42 lung cancer tissue samples to investigate the regulatory effects of neferine on TGF-β and MST1. We also treated lung cancer cells with different concentrations of neferine to study its effects on lung cancer cell survival, migration, invasion, and epithelial–mesenchymal transition (EMT) as well as on pyroptosis. Lentivirus-mediated gain-of-function studies of TGF-β and MST1 were applied to validate the roles of TGF-β and MST1 in lung cancer. Next, we used murine transplanted tumor models to evaluate the effect of neferine treatment on the metastatic capacity of lung cancer tissues. With increasing neferine concentration, the viability, migration, invasion, and EMT capacity of A549 and H1299 cells decreased, whereas pyroptosis increased. Neferine repressed TGF-β expression to modulate the induction of reactive oxygen species (ROS) by MST1. Overexpression of TGF-β in either in vitro or mouse-transplanted A549 cells restored the inhibitory effect of neferine on tumor development. Overexpression of MST1 clearly enhanced pyroptosis. Neferine contributed to pyroptosis by regulating MST1 expression through downregulation of TGF-β to induce ROS formation. Therefore, our study shows that neferine can serve as an adjuvant therapy for NSCLC patients.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYST
·
2023
·
IF 4.2
Xiao Yang,Yang Huang,Siyi Yang,Miao Tang,Juan Liu,Jinhui Shen,Huanbao Fa,Danqun Huo,Changjun Hou,Mei Yang
Technological advances in the detection of circulating tumor DNA (ctDNA) have made new options available for diagnosis, classification, biological studies, and treatment selection. However, effective and practical methods for analyzing this emerging class of biomarkers are still lacking. In this work, a fluorescent biosensor was designed for the label-free detection of ctDNA (EGFR 19 del for non-small cell lung cancer, NSCLC). The biosensor was based on the fact that MnO2 nanosheets (MnO2 NSs) have stronger affinity towards single-stranded DNA (ssDNA), as compared with double-stranded DNA (dsDNA). As a high-performance nanoenzyme, MnO2 NSs could oxidize dopamine (DA) into fluorescent polydopamine nanoparticles (FL-PDA NPs), which could be used as a fluorescence signal. The probe ssDNA could be adsorbed on the surface of MnO2 NSs through π–π stacking, and the active site would be masked, causing a lower fluorescence. After the targets were recognized by probe ssDNA to form dsDNA, its affinity for MnO2 NSs decreased and the active site recovered, causing a restored fluorescence. It was verified that Mn ions, •OH radicals and electron transfer were the important factors in the catalytic oxidation of DA. Under the optimal experimental conditions, this biosensor exhibited a detection limit of 380 pM and a linear range of 25–125 nM, providing reliable readout in a short time (45 min). This sensor exhibited outstanding specificity, stability and reproducibility. In addition, this sensor was applied to the detection of ctDNA in serum samples and cell lysates. It is demonstrated that FL-PDA NPs can be used as a fluorescence signal for easy, rapid and label-free detection of ctDNA without any other amplification strategies, and the proposed strategy has great potential for biomarker detection in the field of liquid biopsy.
研究领域:
生物技术
·
生物传感器
·
纳米技术
·
癌症诊断
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR BIOLOGY REPORTS
·
2024
·Vol. 52
·期 1
·1-13
·
IF 2.6
Ming Huiyun,Lu Tingting,Zhou Han,Song Wencheng,Dai Haiming
Background Non-small cell lung cancer (NSCLC) is a type of lung cancer, the incidence and mortality rate have been high, and the use of monotherapy is easy to make patients develop tolerance. Atmospheric pressure plasma (APP) is an emerging technology for killing cancer cells in recent years, and combination of berberine (BBR) mechanism has not been fully elucidated for NSCLC. The article’s primary goal is to investigate the effect of combination on NSCLC and its associated characterization. Methods and results Antiproliferative effects were detected by cell viability assay and colony formation, and flow cytometry analysis of apoptosis and cycling showed that the combination synergistically induced apoptosis. Then, extracellular reactive oxygen species (ROS)levels and DCFH-DA-based kits examined intracellular ROS levels, and their effects on mitochondrial membrane potential were measured. Study reveals that co-induced apoptosis is associated with ROS accumulation. Subsequently, Western blotting (WB) detected the expression of epidermal growth factor receptor (EGFR), and the important signaling pathway proteins Ras/ERK and AKT/mTOR. Results showed that it could downregulation of EGFR protein expression and inhibit of activation of ERK/AKT signaling pathways. Simultaneous wound healing assay and epithelial-to-mesenchymal transition (EMT) marker detection were performed for the assessment of migration and EMT ability of NSCLC cells. Combination therapy inhibited migration and EMT of NSCLC cells. Conclusion The results of this study show that the combination can synergistically induce apoptosis of NSCLC by regulating ROS production. EGFR downregulation and AKT/ERK signaling pathway inhibition are linked to the synergistic effect.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2024
·
IF 10.7
Xiao Yang,Liangyi Zhao,Siyi Yang,Miao Tang,Huanbao Fa,Danqun Huo,Changjun Hou,Mei Yang
The detection of circulating tumor DNA (ctDNA), as a practical liquid biopsy technique, was of great significance for the study of cancer diagnosis and prognosis. However, reported methods for detection ctDNA still have some limitations, such as tedious process and high cost. In this study, CsPbBr 3 nanosheet (CsPbBr 3 NS) with high water stability was prepared by etching, and its fluorescence intensity could be stably stored for 1 year. The Ti 3 C 2 T x possessed high quenching efficiency for CsPbBr 3 NS and the HOMO-LUMO orbital study revealed that the PET mechanism was responsible for fluorescence quenching. And the Ti 3 C 2 T x showed stronger affinity towards single-stranded DNA (ssDNA), as compared with double-stranded DNA (dsDNA). The probe ssDNA could be adsorbed on the surface of Ti 3 C 2 T x through π-π stacking. After the targets were recognized by probe ssDNA to form dsDNA, its affinity with Ti 3 C 2 T x decreased and the active site of Ti 3 C 2 T x recovered, causing a high quenching efficiency on CsPbBr 3 NS. Based on this, a label-free fluorescent biosensor was designed for the sensitive detection of ctDNA ( EGFR 19 Dels for non-small cell lung cancer, NSCLC). Under the optimal experimental conditions, this biosensor exhibited a detection limit of 180 fM and a linear range of 50 pM–350 pM with amplification of magnetic beads through strand displacement reaction. In addition, this sensor was applied to the detection of ctDNA in serum samples and cells lysates. This method for ctDNA detection was expected to have great potential for biomarker detection in the field of liquid biopsy.
研究领域:
癌症诊断
·
纳米技术
·
生物传感器
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2024
·Vol. 25
·期 1
·1-16
·
IF 4.7
Wang Han,Du Xiaohui,Liu Wenwen,Zhang Congcong,Li Ying,Hou Jingwen,Yu Yi,Li Guiru,Wang Qi
BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs.MethodsWe established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment.ResultsBetulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts.ConclusionsBA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.Graphical abstract
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Haoyun Bai,Tong Wu,Yanni Lv,Wenhao Chen,Yuhan Jiang,Fayuan Chen,Ping Su,Heshui Yu,Langchong He,Zheng Li,Shengli Han
Background Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are widely regarded as the most promising strategy to treat non-small cell lung cancer (NSCLC). While the existing development model cannot meet the requirements. Methods Here, we developed a drug prediction and screening platform based on state-of-the-art deep learning (DL) algorithms and cell membrane chromatography (CMC). Using this platform, we discovered several novel EGFR antagonists from massive molecules. The interactions between target compounds and EGFR were investigated using frontal analysis, Surface plasmon resonance analysis, cellular thermal shift assay, and molecule docking. Xenografts models were established to study the anti-tumor activity of most promising compound. Proteomics, immunofluorescence, and Western blots were conducted to explore its mechanism. Results The deep neural network had good performance, with an area under the curve of 0.950 ± 0.012. Among the top 100 molecules predicted by the model, 25 compounds had retention on SNAP-tagged (ST)-EGFR/CMC, of which 12 molecules exhibited significant anti-tumor activity. Interaction analysis revealed that Geraniin, Brazilin, and 7-Epitaxol would directly bind to EGFR and inhibit its activation. 7-Epitaxol exhibited significant anti-tumor activity in vivo and in vitro . 7-Epitaxol combined with EGFR and inhibited its phosphorylation, blocked PI3K/AKT pathways, thereby exerting its anti-tumor activity by promoting autophagy in A549 cells. Conclusion The results provide a novel and powerful platform for drug discovery and development in NSCLC research. By using this platform, Geraniin, Brazilin, and 7-epitaxol were identified as novel EGFR antagonists. We also innovatively demonstrated that 7-epitaxol promotes autophagy in NSCLC.
研究领域:
人工智能
·
计算生物学
·
药理学
·
肿瘤学
·
分子生物学
·
生物信息学
·
药物研发
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2025
·Vol. 192
·期 9
·1-13
·
IF 5.3
He Linxin,Wei Yuxin,Chen Cizhi,Li Chuanhai,Xu Ying,Chen Mei
A sensitive dual-target electrochemical biosensor was developed integrating circular bipedal DNA walkers with a three-dimensional hollow carbon nanospheres-tetrametallic nanoparticle (3D HCNs-TT NPs) modified platform, enabling concurrent detection of two critical epidermal growth factor receptor (EGFR) exon 19 mutations: E746_A750 deletion (Mut DNA A) and L747_S752delinsS (Mut DNA B). The circular bipedal DNA walkers address the limitations of low amplification efficiency in traditional single-legged DNA walkers and mitigate the sensitivity reduction caused by excessively long walking strands. Additionally, we used the 3D HCNs-TT NPs nanocomposite materials to modify the electrodes, which significantly increased the electron transfer rate and provided more active sites for molecular probe loading, thereby further enhancing the performance of the detection platform. This biosensor demonstrated good performance, with detection limits as low as 3.4 fM (Mut DNA A) and 2 fM (Mut DNA B) (S/N = 3). The designed sensor was applied for detection using clinical samples, including cells with gene mutations and diluted human serum, and these results confirm the sensor’s potential for clinical translation, offering a potential tool for early non-small cell lung cancer (NSCLC) diagnosis and personalized tyrosine kinase inhibitors (TKI) therapy guidance. Graphical abstract
研究领域:
生物传感器
·
分子诊断学
·
纳米技术
·
癌症遗传学
·
电化学
·
DNA纳米技术
·
临床诊断学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）