EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Yuehua Yu,Zixuan Li,Yuan He,Ji Huang,Zhenxiao Sun
Lung adenocarcinoma is a highly fatal carcinoma worldwide with limited therapeutic options. We identified EGFR/ERBB2 as promising dual targets through integrative analysis of clinical data and TCGA database. Molecular docking and cytotoxicity screening of FDA-approved drugs identified Ebastine as a potent dual-targeting agent. Ebastine significantly inhibited NCI-H1975 cell viability (EGFR-mutant with high EGFR/ERBB2 expression), induced ROS elevation, decreased mitochondrial membrane integrity, and triggered apoptosis. Western blot revealed that Ebastine suppressed phosphorylation of EGFR, ERBB2, ERK1/2 and AKT. In xenograft models, Ebastine significantly inhibited NCI-H1975 tumor growth with no significant impact on body weight. Histopathological and immunohistochemical analyses showed reduced Ki67 expression and increased tumor cell apoptosis in Ebastine-treated tumors. Notably, Ebastine promoted macrophage infiltration and M1 polarization both in vivo and in vitro . Our findings establish Ebastine as a promising therapeutic candidate for EGFR/ERBB2-mutant lung adenocarcinoma through a unique dual-targeting approach that combines direct tumor cell inhibition with enhancement of anti-tumor immunity.
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高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Zhitao Zhu,Zhengzhong Lv,Yurong Fan,Hongyuan Wen,Yuqi Zhang,Yirui Guo,Miao Li,Xingxiang Ren,Haibin Shi,Guohua Fan
Non-small cell lung cancer (NSCLC) is a cancer with high morbidity and mortality and faces multiple clinical challenges in early diagnosis, efficient treatment, targeted drug selection, and drug resistance. Herein, neovascularization and EGFR dual-targeting gold nanotheranostic system Bev-Au-CD(Osi) is designed and fabricated for epidermal growth factor receptror (EGFR)-mutated NSCLC treatment. This nanosystem consists of gold nanoparticle as drug nanocarrier and imaging contrast agent, Bevacizumab for targeting tumor neovascularization, and β-cyclodextrin (β-CD) as the cage for encapsulating EGFR mutant inhibitor Osimertinib. Taking advantage of the specific targeting ability of Bevacizumab to vascular endothelial growth factor (VEGF), Bev-Au-CD(Osi) nanoparticles target and accumulate at the tumor site for sensitive computed tomography (CT)/photoacoustic (PA) imaging of tumors. More notably, the sustained release of Osimertinib efficiently suppresses tumor growth through inhibiting angiogenesis and blocking the EGFR signaling pathway, significantly enhancing the therapeutic efficacy of NSCLC tumor in living mice. This work provides a powerful and universal nanotheranostic system for the precise treatment of EGFR-mutated NSCLC.
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Materials Today Bio
·
2026
·
IF 11
Fangying Zheng,Yanyun Su,Xianbin Sun,Ding Tan,Ya Wang,Xiumei Li,Yu Gao
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are primary treatments for EGFR-mutated non-small cell lung cancer (NSCLC), but acquired resistance limits efficacy. To address this challenge, we developed CsO/IGA, a multifunctional nanoplatform combining osimertinib (AZD9291) with an indocyanine green-gadolinium (ICG-Gd) probe via oleanolic acid (OA)-modified chitosan encapsulation, integrating fluorescence/magnetic resonance imaging (FLI/MRI) with chemo-phototherapy and tumor microenvironment (TME) modulation. CsO/IGA (∼100 nm) demonstrated excellent stability and generated both singlet oxygen and hyperthermia under 808 nm irradiation. The nanoplatform exerted efficient anti-cancer effects to overcome resistance through reactive oxygen species induction, mitochondrial membrane potential reduction, and EGFR/phosphorylated EGFR downregulation in sensitive and resistant NSCLC cells. Notably, the OA component suppressed cancer-associated fibroblasts and α-smooth muscle actin expression, remodeling the TME to enhance tumor penetration. In vivo studies confirmed tumor-specific accumulation and deep penetration, FLI/MRI capability, and superior antitumor efficacy through chemo-phototherapy synergy. This work presents a promising OA-integrated theranostic strategy integrating targeted therapy, phototherapy, TME modulation, and diagnostic imaging for overcoming EGFR-TKI resistance in NSCLC.
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BIOORGANIC & MEDICINAL CHEMISTRY
·
2018
·
IF 2.881
Ping Zhou,Gang Chen,Minqi Gao,Jiaquan Wu
Osimertinib has been approved as a first-line treatment for non-small-cell lung cancer (NSCLC) patients whose tumor carries EGFR activation and / or resistant mutations. To mitigate Osimertinib’s toxicity caused by AZ5104, the N-demethylation metabolite of Osimertinib, we designed and synthesized a series of Osimertinib analogs with different headpieces. In vitro and in vivo analysis rendered a potential clinical candidate C-005 which had pyrrolo-pyridine headpiece. Biochemically, C-005 and its main human hepatocyte metabolite showed over 30 fold selectivity of L858R/T790M mutant EGFR over WT EGFR. Such selectivity profile was retained at cellular level. In general, C-005 is 2-14 fold more selective than Osimertinib in a panel of WT EGFR cancer cell lines. Furthermore, C-005 demonstrated robust antitumor efficacy and good tolerability in NCI-H1975, PC-9 and HCC827 xenograft mouse models, making it a potential candidate for human test in clinical.
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高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 11
·4962-4973
·
IF 5.31
Mingyu He,Gege Yan,Yang Wang,Rui Gong,Hong Lei,Shuting Yu,Xiaoqi He,Guanghui Li,Weijie Du,Tianshuai Ma,Manqi Gao,Meixi Yu,Shenzhen Liu,Zihang Xu,Elina Idiiatullina,Naufal Zagidullin,Valentin Pavlov,Benzhi Cai,Ye Yuan,Lei Yang
Osteosarcoma (OS) is the most common primary malignant bone tumour in adolescence. Lately, light-emitting diodes (LED)-based therapy has emerged as a new promising approach for several diseases. However, it remains unknown in human OS. Here, we found that the blue LED irradiation significantly suppressed the proliferation, migration and invasion of human OS cells, while we observed blue LED irradiation increased ROS production through increased NADPH oxidase enzymes NOX2 and NOX4, as well as decreased Catalase (CAT) expression levels. Furthermore, we revealed blue LED irradiation-induced autophagy characterized by alterations in autophagy protein markers including Beclin-1, LC3-II/LC3-I and P62. Moreover, we demonstrated an enhanced autophagic flux. The blockage of autophagy displayed a remarkable attenuation of anti-tumour activities of blue LED irradiation. Next, ROS scavenger N-acetyl-L-cysteine (NAC) and NOX inhibitor diphenyleneiodonium (DPI) blocked suppression of OS cell growth, indicating that ROS accumulation might play an essential role in blue LED-induced autophagic OS cell death. Additionally, we observed blue LED irradiation decreased EGFR activation (phosphorylation), which in turn led to Beclin-1 release and subsequent autophagy activation in OS cells. Analysis of EGFR colocalization with Beclin-1 and EGFR-immunoprecipitation (IP) assay further revealed the decreased interaction of EGFR and Beclin-1 upon blue LED irradiation in OS cells. In addition, Beclin-1 down-regulation abolished the effects of blue LED irradiation on OS cells. Collectively, we concluded that blue LED irradiation exhibited anti-tumour effects on OS by triggering ROS and EGFR/Beclin-1-mediated autophagy signalling pathway, representing a potential approach for human OS treatment.
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ONCOGENE
·
2025
·
IF 7.3
Li Honghao,Wu Junfeng,Dai Hua,Li Jiaming,Bai Xiaoyan,Sun Yueli,Lin Jiaxin,Li Yangsi,Li Peng,Shi Lingchao,Wang Zhen,Tu Haiyan,Ke Ee
Indolent lung cancer is characterized by slow progression, and the patient may die of other causes before it becomes symptomatic. The increasing usage of lung cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung cancer patients. In this study, we performed high-throughput whole-exome sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4 , rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung cancer cell growth in vitro and in vivo. With the EGFR L858R -driven lung cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung cancer and to avoid overdiagnosis. Graphical : Germline variation rs74955204 (p.G121E, c.362 G > A) in PDZRN4 significantly upregulated PDZRN4 expression and resulted in indolent growth of LUAD. Overexpressed PDZRN4 inhibits the ubiquitylation of HIF-1A by TRIM28, activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, thus restricting lung cancer cell growth.
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EXPERIMENTAL DERMATOLOGY
·
2020
·Vol. 30
·期 7
·932-942
·
IF 3.368
Aimin Liu,Buxin Zhang,Wei Zhao,Yuanhui Tu,Qingxing Wang,Jing Li
Psoriasis is a chronic inflammatory disease characterized by abnormal hyperproliferation and differentiation. The object of this study is to explore the role of microRNA-215-5p in psoriasis-like inflammation. The expression of miR-215-5p was found to be down-regulated in pro-inflammatory factor-stimulated HaCaT cells and imiquimod (IMQ)-treated skin tissues. Overexpression of miR-215-5p suppressed the proliferation and cell cycle progression of HaCaT cells. Further, miR-215-5p agomir alleviated the disease severity, pathological features and Ki67 positive cells in IMQ-treated mice. Luciferase assay confirmed that miR-215-5p could bind to the 3′UTR of DYRK1A. The in vitro and in vivo results showed that miR-215-5p negatively regulates DYRK1A, which further inhibited EGFR and its downstream signalling pathways, AKT and ERK. Collectively, our results provide evidence that overexpression of miR-215-5p inhibits the proliferation of HaCaT cells and alleviates psoriasis-like inflammation partly by DYRK1A mediated inhibition of the EGFR signalling pathway. miR-215-5p may serve as a novel small molecule for therapeutic intervention in psoriasis.
研究领域:
分子生物学
·
皮肤科
·
炎症性疾病
·
微小RNA研究
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Qiqi Yang,Yuan Yao,Junping Wang,Mengdi Pang,Jinyan Wu,Fusheng Yin,Jun He,Yanyan Wang,Weidong Chen
Non-small cell lung cancer (NSCLC) is characterized by a complex pathogenesis and high mortality. Targeted drug therapy represents a precise method of treatment. However, Improving sensitivity to targeted agents is currently a major challenge in clinical tumor therapy. Neogambogic acid (NGA), a bioactive compound isolated from the Traditional Chinese Medicine (TCM) Gamboge, has shown potential in NSCLC treatment. Nonetheless, the mechanism by which NGA enhances the sensitivity of NSCLC to the targeted drug Almonertinib remains unclear. This study aimed to elucidate the mechanisms underlying the ability of NGA to enhance the sensitivity of NSCLC to Almonertinib, revealing the synergistic effect exerted by the combination therapy. We established a subcutaneous grafted tumor model of mouse lung cancer by injecting Lewis cells, and evaluated the therapeutic efficacy in vivo . The study demonstrated that NGA combined with Almonertinib effectively suppressed NSCLC tumor growth by promoting cancer cell apoptosis and reducing serum tumor marker levels. In vitro experiments revealed that this combination synergistically inhibited lung cancer cell proliferation and induced apoptosis. Mechanistically, NGA demonstrated the ability to bind to Pregnane X receptor (PXR), regulating the expression of drug-metabolizing enzymes and transporters. We further validated this effect using PXR agonists and inhibitors in A549 cells. Additionally, the combination of NGA with Almonertinib significantly inhibited aberrant EGFR activation and downstream PI3K/AKT signaling, leading to enhanced apoptosis. This study demonstrated that the combination of NGA and Almonertinib inhibited the expression of CYP3A4, P-gp, and BCRP via PXR modulation. Meanwhile, it inhibited the EGFR/PI3K/AKT pathway and enhanced the sensitivity of NSCLC to Almonertinib, exerting synergistic anti-tumor effects. Our findings suggest a promising strategy for integrating active TCM components with targeted therapy in NSCLC management.
研究领域:
肿瘤学
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药理学
·
分子生物学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Bing Feng,Yanjing Lu,Bowen Zhang,Ying Zhu,Zuqing Su,Lipeng Tang,Laijun Yang,Tong Wang,Chunxia He,Chutian Li,Jie Zhao,Xirun Zheng,Guangjuan Zheng
Emerging evidence suggests that gut microbiota and its metabolites significantly influence the effectiveness of EGFR-TKIs (e.g., gefitinib, erlotinib) in lung cancer treatment. Plant polysaccharides can interact with gut microbiota, leading to changes in the host-microbe metabolome that may affect drug metabolism and therapeutic outcomes. Our previous research demonstrated the efficacy of basil polysaccharide (BPS) in treating various cancers by regulating hypoxic microenvironment and inhibiting epithelial-mesenchymal transition process. However, the potential impact of BPS on gut microbiota has not been thoroughly explored. In this study, we employed an immunodeficient gefitinib-resistant xenograft mouse model to explore whether BPS enhances the antitumor effects of gefitinib. A multi-omics approach, including 16S rDNA amplicon sequencing and LC-MS, was used to elucidate these synergistic effects. Our findings indicate that BPS can enhance tumor responsiveness to gefitinib by modulating the gut microbiota and its metabolites through multiple metabolic pathways. These changes in gut microbiota and metabolites could potentially affect cancer related signaling pathway and lung resistance-related protein, which are pivotal in determining the efficacy of EGFR-TKIs in cancer treatment.
研究领域:
肿瘤学
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药理学
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微生物学
·
代谢组学
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BIOMEDICAL CHROMATOGRAPHY
·
2025
·Vol. 39
·期 2
·e6063
·
IF 1.7
Fan Tang,Xiaoli Hou,Jiajie Chen,Yasen Cao,Yixia Wang,Hong Cheng
Mobocertinib is a potent selective tyrosine kinase inhibitor approved for the treatment of non–small cell lung cancer with activating EGFR exon 20 insertions. The aim of this study was to develop a procedure for liquid chromatography tandem mass spectrometry (LC-MS/MS) for the determination of mobocertinib and its metabolite desmethyl-mobocertinib in human plasma. The human plasma samples were precipitated with acetonitrile and analyzed using a Waters ACQUITY BEH C 18 column coupled to a triple quadrupole mass spectrometer. Separation was executed using the acetonitrile–0.1% formic acid solution with gradient elution, at a flow rate of 0.4 mL/min. Mobocertinib and desmethyl-mobocertinib were monitored by multiple reaction monitoring (MRM) with m / z 586.5 > 72.2 and 572.4 > 473.2, respectively. The procedure demonstrated excellent linearity ( r > 0.997) within the concentration range of 0.1–200 ng/mL for both analytes. Precision in relative standard deviation was < 9.37% for mobocertinib and < 12.03% for desmethyl-mobocertinib. Accuracy in relative error was within −7.23% to 9.18% for mobocertinib and −2.78% to 9.87% for desmethyl-mobocertinib. Extraction recovery was > 80% for both analytes. The validated LC-MS/MS method was successfully applied to the pharmacokinetic study of mobocertinib and desmethyl-mobocertinib in healthy human volunteers with K 2 EDTA as anticoagulant after a single dose of mobocertinib (160 mg).
研究领域:
药理学
·
分析化学
·
肿瘤学
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
·
2019
·
IF 1.17
Yun-Mei Liu,Yang Li,Rong-Fang Liu,Jie Xiao,Bin-Ning Zhou,Qi-Zhi Zhang,Jian-Xin Song
Chrysin amino acid derivatives were synthesized to evaluate for their antiproliferative activities. Among them, N-(7-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)valeryl)-L-leucine (8c) displayed the most remarkable inhibitory activities against MCF-7 cells with IC50 values of 16.6 μM. Preliminary mechanistic studies showed that 8c could inhibit the colony formation and migration of MCF-7 cells. Flow cytometry analysis demonstrated that 8c mediated cell apoptosis and the prolongation of cell cycle progression in G1/S-phase against MCF-7 cells. Besides, 8c displayed the moderate inhibition against EGFR. Western blot assay suggested that 8c significantly inhibited EGFR phosphorylation. Molecular docking showed that 8c can bind the EGFR kinase well.
研究领域:
药理学
·
肿瘤学
·
分子生物学
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ANALYTICA CHIMICA ACTA
·
2026
·
IF 6.1
Pengxiao Guo,Jianshe Li,Huijing Du,Kanglei Wang,Lei Zhang,Shuguang Li
Traditional surface plasmon resonance (SPR) sensors generally rely on a single sensing interface, making it difficult to achieve selective enhancement of different response mechanisms, thereby limiting their multiparameter detection capability and sensing performance. In this work, a multi-mechanism signal amplification SPR fiber-optic sensing platform based on interface-cooperative regulation is proposed for the simultaneous detection of epidermal growth factor receptor (EGFR) exon 20, pH, and temperature, while enabling real-time temperature compensation. By constructing functional interfaces with distinct physicochemical characteristics, synergistic signal amplification through multiple sensing mechanisms is achieved. Specifically, the Ag interface utilizes stable Ag–S bonding to enable efficient immobilization of probe DNA for the specific recognition of exon 20; the hydroxyl-rich Ag/TiO 2 interface facilitates the stable assembly of the PAA/CS functional layer to form a pH-responsive channel; and the Ag/MoS 2 /PDMS composite structure provides temperature monitoring and compensation through its thermosensitive characteristics. Meanwhile, the synergistic optical regulation of the high-refractive-index TiO 2 layer and the two-dimensional MoS 2 material enhances the local electromagnetic field and enables effective spectral separation among multiple sensing channels, resulting in improved sensing performance. Experimental results demonstrate average sensitivities of 0.178 nm/nM, −22.59 nm/pH, and −4.439 nm/°C for exon 20, pH, and temperature detection, respectively. By introducing a real-time temperature compensation strategy, the accuracy and reliability of EGFR exon 20 detection are further improved. The proposed sensing platform provides a promising approach for lung cancer biomarker analysis and multimodal physiological monitoring in complex biological environments.
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