NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2024
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IF 3.1
Duan Qiong,Li Ruochen,Wang Mingxiao,Cui Zhenting,Zhu Xia,Chen Fanghong,Han Feng,Ma Jianxin
Phillyrin (PHN), derived from the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a kind of Chinese herbal medicine with the effect of clearing heat, and has been used in China for thousands of years in treating various tumors. However, the mechanism of its main components on non-small cell lung cancer (NSCLC) remains unclear. PHN is a distinct component extracted from Forsythia suspensa with promising anti-cancer activity against various tumor types. This study sought to elucidate the promising effects of PHN on NSCLC. Based on network pharmacology results, we identified potential PHN targets and pathways for NSCLC treatment. CCK-8 assay, wound healing assay, apoptosis assay, western blot, and in vivo experiments verified the inhibitory effect of PHN on NSCLC. Network pharmacology identified 160 potential PHN targets, 955 NSCLC-related targets, and 54 common targets, along with 132 pathways and 2 core genes. Biological experiments demonstrated that PHN significantly inhibited the growth and migration of A549 and LLC cells while promoting their apoptosis. Western blot analysis revealed down-regulation of AKT, HSP90AA1, and CDC37 expression, suggesting that PHN inhibits A549 and LLC cell proliferation by down-regulating the HSP90-AKT pathway. In vivo experiments confirmed that PHN significantly inhibited NSCLC growth with low toxicity. This study, using network pharmacology and biological experiments, verified the effectiveness of PHN against NSCLC through the HSP90-AKT pathway. These findings provide a foundation for further research and analysis.
研究领域:
肿瘤学
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药理学
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分子生物学
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中药学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
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IF 6.8
Jianxia Zhang,Yi Wang,Mengying Wang,Peipei Wang,Hao Yan,Dalong Wang,Jiahao Zheng,Bin Li,Chaoyue Chen,Di Cao,Xiaohui Zheng,Xiaokun Li,Kun Wang,Zhiguo Liu
Fibroblast growth factor receptors (FGFRs) play a critical role in the regulation of cancer cell proliferation, differentiation, and migration. However, the development of acquired resistance to FGFR inhibitors remains a major challenge in treating non-small cell lung cancer (NSCLC), particularly due to mutations at the gatekeeper residue. In this study, we report the discovery of a series of irreversible FGFR inhibitors targeting gatekeeper mutations in FGFR1–3, utilizing a 2,4,5-trisubstituted pyrimidine scaffold. Through rational design, structure–activity relationship optimization, and pharmacokinetic evaluation, compound ng 12l emerged as a promising candidate. It demonstrated potent inhibition of FGFR1–3 gatekeeper mutations in vitro along with favorable pharmacokinetic properties. The efficacy of 12l in targeting FGFR1 gatekeeper mutations was confirmed in assays using L6-FGFR1V561M/F cells. Furthermore, in xenograft models using both H1581 and L6-FGFR1V561M cells, 12l exhibited robust anti-tumor activity with minimal toxicity. These findings position 12l as a promising therapeutic agent for overcoming gatekeeper-mediated resistance in NSCLC.
研究领域:
肿瘤学
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药物化学
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药理学
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癌症生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
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IF 3.831
Chen Donglai,Zhang Fuquan,Wang Jinhui,He Hua,Duan Shanzhou,Zhu Rongying,Chen Chang,Yin Lichen,Chen Yongbing
Background: Erlotinib (ELTN)-based targeted therapy as first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung cancers suffers from insufficient selectivity, side effects, and drug resistance, which poses critical challenges in the clinical setting. Acquired resistance of ELTN results in extremely poor prognoses of non-small cell lung cancer (NSCLC) patients, wherein activation of the JAK2/STAT3 signaling pathway has been proven to induce acquired ELTN resistance.Methods: In this study, we developed a nanoparticle (NP) delivery system based on Food and Drug Administration (FDA)-approved poly(ethylene glycol) (PEG)-poly(lactic acid) (PLA) for the co-delivery of ELTN and fedratinib (FDTN, a small-molecular, highly selective JAK2 inhibitor). Both ELTN and FDTN could be encapsulated into the PEG-PLA NPs via optimization of the encapsulation method. The effect of NPs on NSCLC cells was evaluated by MTT assay. Western blotting was performed to study the molecular mechanisms of NPs inhibiting the downstream pathways of EGFR in vitro. The histological analysis and protein expression in vivo were assessed by hematoxylin/eosin (H&E) staining and immunohistochemistry, respectively.Results: The drug cargoes exhibited great stability, and could be released more efficiently in the acidic tumorous condition. Mechanistic study showed that FDTN notably down-regulated the expression levels of proteins in the JAK2/STAT3 signaling pathway, including p-EGFR, p-JAK2, p-STAT3 and Survivin, therefore reversing the ELTN resistance. As a result, synergistic anti-cancer effect was achieved by PEG-PLA NPs encapsulating both ELTN and FDTN in ELTN-resistant NSCLC tumors both in vitro and in vivo, and lower systemic side effect was noted for the co-delivery NPs compared to free drugs.Conclusion: This study provides a promising approach to overcome the ELTN resistance in the treatment of NSCLC, and the use of FDA-approved materials with clinically applied/investigated chemical drugs may facilitate the translation of the current delivery system.
研究领域:
药学
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肿瘤学
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纳米技术
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2020
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IF 4.545
Song Chen,Yujie Ren,Peng Duan
Lung cancer still remains a leading cause of cancer mortality in the world. Obatoclax mesylate (OM), a B cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) family antagonist, is a potential antitumor drug. However, its poor aqueous solubility restricts its clinical application. Although these inherent defects, nanotechnology can be used to improve the solubility and tumor target of OM, promoting its antitumor efficiency. In the present study, the poly(lactic-coglycolic acid) (PLGA) was used and combined with red blood-cell membrane (RBCm) to explore if OM-loaded RBCm nanoparticles could improve the antitumor efficacy of OM for the treatment of lung cancer with relatively lower side effects compared with the free OM. The good physicochemical stability of the prepared RBCm-OM/PLGA nanoparticles was confirmed, and the optimal size of 153 nm was screened out, along with sustained drug release behavior. We found that RBCm-OM/PLGA nanoparticles effectively reduced the proliferation of lung cancer cells. Additionally, RBCm-OM/PLGA nanoparticles considerably induced apoptosis in lung cancer cells by reducing Bcl-2 expression levels, accompanied with the improved Cyto-c releases in cytoplasm and Caspase-3 activation. Mitochondrial membrane potential was also obviously impaired in lung cancer cells incubated with RBCm-OM/PLGA nanoparticles. Compared with free OM, RBCm-OM/PLGA nanoparticles could greatly prolong the drug circulation time in vivo and upgraded the drug concentration accumulated in tumor tissue. Furthermore, RBCm-OM/PLGA nanoparticles exerted stronger antitumor efficacy in vivo against lung cancer progression with superior safety. Therefore, RBCm-OM/PLGA nanoparticles provided new potential for lung cancer therapy with the improved safety and therapeutic effect.
研究领域:
药理学
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肿瘤学
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纳米技术
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生物医学工程
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2022
·Vol. 10
·期 43
·8931-8944
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IF 7.571
Shengjie Ge,Yujie Wang,Zhiyue Li,Bin Lu,Jinhua Zhu,Hongmei Lu,Xiaowei Cao,Yayun Qian
In this study, we apply catalytic hairpin assembly (CHA) as the signal amplification strategy for the quantification of carcinoembryonic antigen (CEA) and cytokeratin fragment antigen 21-1 (CYFRA21-1) with a surface-enhanced Raman scattering (SERS) microfluidic chip (LoC-SERS) as the carrier. Herein, antibody–DNA conjugates are designed to assist the application of CHA amplification in protein detection. In the presence of protein biomarkers, antibody–DNA conjugates can specifically bind to the target proteins, forming the antigen@antibody–DNA conjugates. The terminal free part of the DNA on the conjugates can trigger the CHA events to connect SERS nanotags to capture nanoprobes. Then, micro-magnet can gather the CHA products in a rectangular chamber, resulting in the aggregation of SERS nanotags, which can ultimately generate abundant “hot spots” for SERS signal enhancement. Using this strategy, CEA and CYFRA21-1 can be successfully determined with a limit of detection (LOD) as low as pg mL−1, much lower than recently reported methods. Meanwhile, a non-small cell lung cancer (NSCLC)-xenografted mouse model was established, and SERS was applied to analyze the expression level of CEA and CYFRA21-1 in tumorigenesis and development. The comparison between SERS results and those of the ELISA method demonstrated a high degree of consistency, suggesting that the proposed CHA-assisted LoC-SERS device has satisfying accuracy. Thus, introducing the CHA strategy via the design of antibody–DNA conjugates opens new gates to ultra-sensitive and specific SERS detection of protein biomarkers.
研究领域:
生物医学工程
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分析化学
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癌症研究
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分子生物学
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DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
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2024
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IF 10.7
Xianglei Fu,Yanbin Shi,Zili Gu,Hengchang Zang,Lian Li,Qingjie Wang,Yongjun Wang,Xiaogang Zhao,Hang Wu,Shengnan Qiu,Yankun Zhang,Jiamin Zhou,Xiangqin Chen,Hua Shen,Guimei Lin
Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.
研究领域:
肿瘤学
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药理学
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生物医学工程
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免疫疗法
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biomed Research International
·
2021
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IF 3.411
Ling Kui,Min Li,Xiaonan Yang,Ling Yang,Qinghua Kong,Yunbing Pan,Zetan Xu,Shouling Wang,Dandan Mo,Yang Dong,Yao Liu,Jianhua Miao
Lung cancer is known as the leading cause which presents the highest fatality rate worldwide; non-small-cell lung cancer (NSCLC) is the most prevalent type of lung carcinoma with high severity and affects 80% of patients with lung malignancies. Up to now, the general treatment for NSCLC includes surgery, chemotherapy, and radiotherapy; however, some therapeutic drugs and approaches could cause side effects and weaken the immune system. The combination of conventional therapies and traditional Chinese medicine (TCM) significantly improves treatment efficacy in lung cancer. Therefore, it is necessary to investigate the chemical composition and underlying antitumor mechanisms of TCM, so as to get a better understanding of the potential natural ingredient for lung cancer treatment. In this study, we selected 78 TCM to treat NSCLC cell line (A549) and obtained 92 transcriptome data; differential expression and WGCNA were applied to screen the potential natural ingredient and target genes. The sample which was treated with A. pierreana generated the most significant DEG set, including 6130 DEGs, 2479 upregulated, and 3651 downregulated. KEGG pathway analyses found that four pathways (MAPK, NF-kappa B, p53, and TGF-beta signaling pathway) were significantly enriched; 16 genes were significantly regulated in these four pathways. Interestingly, some of them such as EGFR, DUSP4, IL1R1, IL1B, MDM2, CDKNIA, and IDs have been used as the target biomarkers for cancer diagnosis and therapy. In addition, classified samples into 14 groups based on their pharmaceutical effects, WGCNA was used to identify 27 modules. Among them, green and darkgrey were the most relevant modules. Eight genes in the green module and four in darkgrey were identified as hub genes. In conclusion, we screened out three new TCM (B. fruticose, A. pierreana, and S. scandens) that have the potential to develop natural anticancer drugs and obtained the therapeutic targets for NSCLC therapy. Our study provides unique insights to screen the natural components for NSCLC therapy using high-throughput transcriptome analysis.
研究领域:
癌症生物学
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药理学
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分子生物学
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生物信息学
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传统中药
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DOI
PubMed
高影响因子
LANGMUIR
·
2025
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IF 3.9
Bolin Yue,Tingli Wang,Mengke Zhang,Xiaoyu Wu,Xu Xu,Zequan Li,Bohan Ye,Lei Liu,Shiyong Song
Proteolysis-targeting chimeric (PROTAC) technology represents a groundbreaking approach with immense potential for treating a wide range of diseases. However, its clinical application is often limited by challenges in solubility and permeability. Herein, we have developed an innovative three-in-one nanoparticulate therapeutic agent tailored for non-small-cell lung cancer (NSCLC). This agent features a PROTAC molecule derived from ceritinib, designated as 27B, serving as a targeted degrader of anaplastic lymphoma kinase (ALK). 27B is self-assembled with vitamin A palmitate (VAP) and vitamin E poly(ethylene glycol) succinate (TPGS) to form stable nanoparticles (BVT-NPs) that exhibit a uniform spherical morphology, excellent storage stability, and robust plasma stability. With an average particle size of approximately 130 nm and a loading capacity of 27B of 20%, BVT-NPs demonstrate a pH-responsive drug release profile. In vitro studies reveal that BVT-NPs significantly inhibit the proliferation of H3122 cells more effectively than free 27B, indicating a synergistic antitumor effect. Western blot analysis further confirms the superior efficacy of BVT-NPs in downregulating ALK and P-glycoprotein and upregulating Caspase-3. BVT-NPs markedly suppress tumor growth without inducing significant tissue toxicity. This carrier-free, multifunctional nanoparticulate system integrates PROTAC-mediated protein degradation with chemotherapy, thereby improving the PROTAC absorption and generating a synergistic therapeutic effect against NSCLC.
研究领域:
癌症治疗
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纳米医学
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药理学
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生物化学
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药物递送
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DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
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2024
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IF 3.8
Jie Zhang,Xiaoling Zang,Peng Jiao,Jiangyu Wu,Wei Meng,Lizhen Zhao,Zhihua Lv
Abnormal lipid metabolism plays an important role in cancer development. In this study, nontargeted lipidomic study on 230 tissue specimens from 79 nonsmall cell lung cancer (NSCLC) patients was conducted using ultraperformance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS). Downregulation of sphingosine and medium–long-chain ceramides and short–medium-chain acylcarnitine, upregulation of long-chain acylcarnitine C20:0, and enhanced histamine methylation were revealed in NSCLC tissues. Compared with paired noncancerous tissues, adenocarcinoma (AC) tissues had significantly decreased levels of sphingosine, medium–long-chain ceramides (Cer d18:1/12:0 and Cer d16:1/14:0, Cer d18:0/16:0, Cer d18:1/16:0, Cer d18:2/16:0, Cer d18:2/18:0), short–medium-chain (C2–C16) acylcarnitines, LPC 20:0 and LPC 22:1, and significantly increased levels of the long-chain acylcarnitine C20:0, LPC 16:0, LPC P-16:0, LPC 20:1, LPC 20:2, glyceroPC, LPE 16:0, and LPE 18:2. In squamous cell carcinoma (SCC) tissues, sphingosine, Cer d18:2/16:0 and Cer d18:2/18:0, and short–medium-chain acylcarnitines had significantly lower levels, while long-chain acylcarnitines (C20:0, and C22:0 or C22:0 M), LPC 20:1, LPC 20:2, and N1,N12-diacetylspermine had significantly higher levels compared to controls. In AC and SCC tissues, the levels of LPG 18:0, LPG 18:1, and LPS 18:1 were significantly decreased, while the levels of ceramide-1-phosphate (C1P) d18:0/3:0 or LPE P-16:0, N1-acetylspermidine, and 1-methylhistamine were significantly increased than controls. Furthermore, an orthogonal partial least-squares-discriminant analysis (OPLS-DA) model based on a 4-lipid panel was established, showing good discrimination ability between cancerous and noncancerous tissues.
研究领域:
癌症生物学
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脂质组学
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质谱分析
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产品关联
DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2023
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IF 4
Zhenzhen Pan,Qiufang Chen,Xiulan Zheng,Kai Wang,Yalei Duan,Kang Xiao,Zhirong Jia,Xuansheng Ding
Background Although gefitinib brings about tremendous advances in the treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, most of patients become incurable due to drug resistance. JuBei oral liquid (JB) has been widely used to treat pneumonia in clinic. Components of JB were reported to induce apoptosis in NSCLC, which indicated that JB could be a potential antitumor agent for NSCLC patients. In this study, we investigated the effect of JB on gefitinib-sensitive PC-9 and gefitinib-resistant PC-9/GR, H1975 cells as well as its underlying molecular mechanisms.Methods PC-9, PC-9/GR and H1975 cells were treated with JB, LY294002, SCH772984, gefitinib alone or in combination. Then, cell viability, colony formation, cell death, expression of mitochondria-dependent pathway proteins, expression of EGFR, PI3K/AKT, MAPK signal pathway proteins, Bcl-2 mitochondrial translocation, ROS generation and cell apoptosis were examined by MTT, colony forming, live/dead cell staining, Western blot, immunofluorescence and flow cytometry assay.Results Our results showed that JB significantly induced cell growth inhibition and apoptotic cell death in PC-9, PC-9/GR and H1975 cells. JB activated mitochondria-mediated apoptotic pathway through inhibiting Bcl-2 mitochondrial translocation while inducing Bax translocated into mitochondria along with accumulated ROS production, thereby increasing the release of cytochrome c, subsequently cleaving procaspase9 into cleaved-caspase9 and then cleaving procaspase3 into cleaved-caspase3. Furthermore, the employment of protein kinase inhibitors LY294002 and SCH772984 revealed that the induction of mitochondria-mediated apoptosis by JB was reliant on inactivation of PI3K/AKT and MAPK signal pathways. Moreover, JB could synergize with gefitinib to induce apoptosis in PC-9, PC-9/GR and H1975 cells.Conclusion These data indicated that JB could be a potential therapeutic agent for NSCLC patients harboring EGFR mutations as well as those under gefitinib resistance.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 7
·e70539
·
IF 4.2
Tianyi Ji,Xiangying Li,Jiachen Li,Guan Wang
Wnt signalling is a highly conserved signalling pathway that plays an important role in a variety of biological processes. Frizzled (Fzd) family proteins are receptors for Wnt ligands. The physiological processes involved in mature trafficking of Fzd proteins remain elusive. Here, we identified asparagine residues 59 and 144 as the N-glycosylation modification sites of Fzd4. Sequence analysis of Fzd4 in different species showed that the two asparagine residues were highly conserved. N-glycosylation modification of Fzd4 is indispensable for its maturation and transport to the plasma membrane. N-glycosylation modification enhances the stability of Fzd4 and is also necessary for Fzd4 activity, which promotes Fzd4 interaction with Wnt ligands and co-receptor Norrin. Knockout of Fzd4 in the non-small cell lung cancer (NSCLC) cell line A549 followed by replenishment of Fzd4 glycosylation site mutants inhibited the growth and migration ability of A549 cells in vitro and in vivo. In summary, we identified N-glycosylation modification sites of Fzd4. N-glycosylation modification of Fzd4 is necessary for its stability and activity. When N-glycosylation modification is absent, Fzd4 cannot mediate the Wnt/β-catenin signalling pathway, which can inhibit the proliferation and migration of NSCLC and provide new targets and strategies for the treatment of NSCLC.
研究领域:
细胞生物学
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分子生物学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Liang Zhang,Huan Liu,Si Jiang,Desheng Li,Xin Li,Maolei Xu,Jianwen Fei,Ling Zhou
Background The natural compound morusin (Mor) acts as a potent tumor suppressor in non-small cell lung cancer (NSCLC), but its potential to sensitize DDP and its direct targets are less understood. This work aims to investigate the DDP-sensitizing effects of Mor and the underlying mechanisms. Methods Cell viability and drug synergy were assessed in NSCLC cells. Ferroptosis was evaluated by measuring lipid reactive oxygen species (ROS), iron accumulation, and the expression of ferroptosis markers. GDF15 was identified as a target via transcriptome sequencing. Its direct binding with Mor was confirmed by molecular docking. The ubiquitin-mediated degradation mechanism and its functional role in ferroptosis were validated using the proteasome inhibitor MG132, alongside GDF15 overexpression and knockdown models. Clinical relevance was assessed using TCGA database analysis. Results Mor induces ferroptosis and significantly augments DDP sensitivity in both NSCLC and cisplatin-resistant A549 cells (A549/DDP). Mechanistically, Mor directly binds to GDF15 and promotes its ubiquitin-mediated degradation. Consequently, GDF15 overexpression reversed Mor-induced cytotoxicity and DDP sensitization. Furthermore, DDP exposure impairs intracellular GDF15 protein levels, and the Mor/DDP combination synergistically suppresses GDF15 in A549 cells. Notably, GDF15 expression is elevated in NSCLC cells compared to normal lung epithelial cells. However, A549/DDP cells exhibit diminished intracellular GDF15 protein relative to parental cells, while GDF15 transcription is upregulated. Knockdown of GDF15 augmented DDP sensitivity in resistant cells. Conclusion Mor reverses DDP resistance by inducing GDF15 degradation and ferroptosis, suggesting that Mor-based combination therapy holds promise in treating NSCLC.
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DOI
PubMed
高影响因子
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