EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2012
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IF 3.346
Lianbao Ye,Yuanxin Tian,Zhonghuang Li,Hong Jin,Zhengguang Zhu,Shanhe Wan,Junyan Zhang,Pengjiu Yu,Jiajie Zhang,Shuguang Wu
Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery . In this study, a series of spiro[indoline-3, 4′-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC 50 values of 0.0147–17 μM in TR-FRET-based assay and IC 50 values of 1.56–1400 μM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met.
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Oncology Letters
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2017
·Vol. 14
·期 2
·2254-2260
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IF 1.39
Ying Liang,Jiao Liu,Ting Liu,Xingsheng Yang
Radiotherapy is preferred to chemotherapy as an adjuvant therapy for postoperative cervical cancer owing to its convenience and minimal effects on various non-targeted systems. The present study sought to investigate whether the utilization of anti-MET proto-oncogene, receptor tyrosine kinase (c-Met) antibodies conjugated to hollow gold nanospheres (anti-c-Met/HGNs) may enhance the efficiency of radiation therapy for cervical cancer. Anti-c‑Met/HGNs were synthesized and confirmed to target c‑Met, which was overexpressed on the cell membrane of multiple malignancies. The successful synthesis of HGNs was observed using transmission electron microscopy (TEM). Overrepresentation of c‑Met in the human cervical cancer cell line CaSki was verified by immunofluorescence. The cellular uptake of HGNs was assessed using inductively coupled plasma atomic emission spectroscopy (ICP‑AES). To assess the toxicity of functionalized gold nanospheres, a cell proliferation and toxicity assay was used and flow cytometry, with staining by propidium iodide (PI), was performed to study the cell cycle changes. Each experiment was conducted on three groups: Control, HGNs alone and anti-c‑Met/HGNs, with each group also assessed with or without X‑rays. The variation of apoptotic rate was observed by flow cytometry using a dual‑staining Annexin V-fluorescein isothiocyanate/PI kit. Expression of apoptosis‑associated proteins was examined by western blot analysis. TEM revealed a number of hollow spheres with cells with an average diameter of 56.25 nm and a mean wall thickness of 6.56 nm. CaSki cells were detected by inverted fluorescence microscopy via a layer of fluorescent green marker, and ICP‑AES confirmed the distinct uptake of anti‑c‑Met/HGNs by each CaSki cell. Anti‑c‑Met/HGNs induced 38.7% of cells to stay in the G2/M phase, whereas the equivalent proportion in the control group was 19.8%. Compared with other groups, CaSki cells treated with anti‑c‑Met/HGNs and 5 Gy X‑ray radiation exhibited a higher apoptosis rate (16.92%) and a higher early apoptotic rate (12.30%) compared with cells under other conditions (control+0 Gy: 3.16 and 1.69%; HGN+0 Gy: 3.98 and 1.94%; anti‑c‑Met/HGN+0 Gy: 3,47 and 1.85%; control+5 Gy: 5.35 and 3.66%; HGN+5 Gy: 7.91 and 4.06%). The anti‑c‑Met/HGN X‑ray‑treated group also evidently overexpressed caspase‑3 and BCL2 associated X, apoptosis regulator. Anti‑c‑Met/HGN may, therefore, aid the sensitivity of radiation therapy in cervical cancer.
研究领域:
肿瘤学
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纳米技术
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放射生物学
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分子生物学
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Nature Chemical Biology
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2024
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IF 12.9
Yang Sihui,Wang Miao,Tian Dawei,Zhang Xiaoyu,Cui Kaiqing,Lü Shouqin,Wang Hong-hui,Long Mian,Nie Zhou
Synthetic signaling receptors enable programmable cellular responses coupling with customized inputs. However, engineering a designer force-sensing receptor to rewire mechanotransduction remains largely unexplored. Herein, we introduce nongenetically engineered artificial mechanoreceptors (AMRs) capable of reprogramming non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, enabling de novo-designed mechanotransduction. AMR is a modular DNA–protein chimera comprising a mechanosensing-and-transmitting DNA nanodevice grafted on natural RTKs via aptameric anchors. AMR senses intercellular tensile force via an allosteric DNA mechano-switch with tunable piconewton-sensitive force tolerance, actuating a force-triggered dynamic DNA assembly to manipulate RTK dimerization and activate intracellular signaling. By swapping the force-reception ligands, we demonstrate the AMR-mediated activation of c-Met, a representative RTK, in response to the cellular tensile forces mediated by cell-adhesion proteins (integrin, E-cadherin) or membrane protein endocytosis (CI-M6PR). Moreover, AMR also allows the reprogramming of FGFR1, another RTK, to customize mechanobiological function, for example, adhesion-mediated neural stem cell maintenance.
研究领域:
生物技术
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细胞生物学
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分子生物学
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纳米技术
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JOURNAL OF INTERNATIONAL MEDICAL RESEARCH
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2022
·
IF 1.573
Wen Zhao,Ye Xu,Qingkui Guo,Wenliang Qian,Chen Zhu,Min Zheng
ObjectiveTo synthesize a novel chalcone-1,3,4-thiadiazole hybrid and investigate its anticancer effects against NCI-H460 cells.Methods(E)-3-(4-bromophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one, 1,3-dibromopropane and 1,3,4-thiadiazole-2-thiol were used as chemical materials to synthesize compound ZW97. The NCI-H460 lung cancer cell line was selected to explore the antitumor effects of compound ZW97 in vitro and in vivo.ResultsCompound ZW97 selectively inhibited cell proliferation against lung cancer cell lines NCI-H460, HCC-44 and NCI-H3122 with IC50 values of 0.15 μM, 2.06 μM and 1.17 μM, respectively. ZW97 suppressed migration and the epithelial–mesenchymal transition process in NCI-H460 cells in a concentration-dependent manner. Based on the kinase activity results and docking analysis, compound ZW97 is a novel tyrosine-protein kinase Met (c-Met kinase) inhibitor. It also inhibited NCI-H460 cell growth in xenograft models without obvious toxicity to normal tissues.ConclusionsCompound ZW97 is a potential c-Met inhibitor that might be a promising agent to treat lung cancer by inhibiting the epithelial–mesenchymal transition process.
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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CHEMICAL RESEARCH IN TOXICOLOGY
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2026
·
IF 4.1
Zihan Li,Boxuan Xie,Xilei Liu,Zihan He,Zhongwei Zhang,Jianming Zhou,Tong Zhou,Huai Wang
As the most frequently occurring cancer worldwide, lung cancer is notoriously diagnosed at advanced stages, resulting in high mortality rates. The primary factor underlying this persistent global health burden remains tobacco consumption. Nicotine, a key component of cigarette smoke, is one of the major contributing factors to the development of lung cancer, but the molecular mechanisms remain incompletely elucidated. α7-nAChR, β2-AR, and HGF/c-Met are known to contribute to lung cancer development, respectively. However, the specific signaling cascade through which they interact in nicotine-induced malignancy is unclear. In this study, using CCK-8 assays across a range of concentrations (0–5 μM), we determined that 1 μM nicotine treatment for 48 h optimally enhances A549 cell proliferation, establishing this condition for subsequent experiments. This study uncovers nicotine’s role in driving malignant behaviors including proliferation, migration, and invasion in nonsmall cell lung cancer A549 cells. Notably, nicotine potently stimulated migration and invasion, accompanied by upregulation of Cyclin D1 and MMP-2, and downregulation of BAX, BAD, and Caspase-3. Mechanistically, nicotine induced synergistic engagement of α7-nAChR and β2-AR, leading to activation of the HGF/c-Met/PI3K/AKT axis and enhancing the secretion of both HGF and MMP-2. Importantly, we reveal a previously unrecognized bidirectional regulatory loop between α7-nAChR and β2-AR that functionally converges on the HGF/c-Met axis, which acts as a critical signaling hub to drive the downstream PI3K/AKT pathway and facilitate tumor progression. Our findings provide the first evidence of a coordinated α7-nAChR/β2-AR interface regulating HGF/c-Met signaling that orchestrates both intracellular signaling and extracellular secretory programs in nicotine-promoted lung cancer progression. This offers innovative insights for identifying potential antitumor therapeutic targets and presents novel perspectives for the prevention and clinical management of lung cancer, particularly in smokers with nonsmall cell lung cancer.
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Science Bulletin
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2025
·
IF 21.1
Min Nie,Danqing Huang,Dandan Wang,Yuanjin Zhao,Lingyun Sun
Refractory wounds (RWs) are a common and severe complication of many diseases; however, the existing therapeutic methods are unsatisfactory in clinical practice. Here, we observed significant downregulation of the hepatocyte growth factor (HGF) in plasma samples from patients with autoimmune diseases. We used electroporation to deliver a plasmid containing HGF to induce its overexpression on mesenchymal stromal cells (MSC HGF ) and loaded them into an injectable hydrogel to treat RWs in patients with clinical autoimmunity. The MSC HGF exhibited stable HGF expression and secretion. In addition, they displayed a self-reinforcing loop, enhanced migration, and improved anti-apoptosis capacity via the autocrine activation of the c-Met-mediated phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Furthermore, the HGF (as well as other bioactive factors) secreted from the MSC HGF significantly augmented the migration and angiopoiesis of vascular endothelial cells, decreased the cellular inflammation of macrophages, and improved extracellular matrix remodeling in fibroblasts. According to these features, we demonstrated that the MSC HGF -loaded injectable hydrogel boosted cellular functions and afforded a long-acting healing efficacy in the treatment of clinical autoimmune patients with RWs. Therefore, the genetically engineered MSC HGF and their dispersed hydrogel system will have clinical significance for wound therapy.
研究领域:
再生医学
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基因治疗
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伤口愈合
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干细胞治疗
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分子生物学
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2022
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IF 5.589
Qiangwei Liang,Yang Lan,Yifan Li,Yongjin Cao,Juan Li,Yanhua Liu
Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG- b -PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG- b -PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOX&Cro in tumor cells. Moreover, the DOX/POEG- b -PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG- b -PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration , concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG- b -PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.
研究领域:
药学
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肿瘤学
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免疫治疗
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药物递送系统
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