EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2025
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IF 4.3
Lei Fang,Ruixue Zhu,Meijing Li,Junhui Ma,Sijun Fan,Xuelian He,Zhongrui Yang,Yakai Yan,Xiang Ma,Guangya Xiang
Proteolysis targeting chimeras (PROTACs) technology is a promising strategy for degrading proteins of interest. Traditional PROTACs, however, often face challenges such as poor solubility, low stability, and off-target toxicity. To address these challenges, we integrated nanotechnology to enhance the delivery of target-protein degraders to the tumor sites, thereby improving their properties. Here, we report silica-based nano-PROTACs (SiPROTACs) that feature multiple ligands on the surface to target and degrade the transmembrane protein epidermal growth factor receptor (EGFR). SiPROTACs, with a diameter of approximately 50 nm, can efficiently bind to EGFR, recruit cereblon (CRBN) to induce EGFR ubiquitination, and facilitate their degradation by proteasomes. In HCC-827 and PC-9 cell lines, SiPROTACs initiated EGFR degradation at a notably low concentration of 50 nM, demonstrating greater efficiency compared to traditional PROTACs. In HCC-827 xenograft tumor-bearing mice, SiPROTACs accumulated at tumor site for at least 48 h and exhibited significant anti-tumor effects in vivo without causing noticeable side effects. These findings suggest a novel approach for the application of PROTACs highlighting their therapeutic potential for the treatment of non-small cell lung cancer (NSCLC).
研究领域:
肿瘤学
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药理学
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纳米医学
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DOI
PubMed
高影响因子
MOLECULES
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2021
·Vol. 26
·期 14
·4361
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IF 4.412
Ya Wang,Xiao-Jing Shen,Fa-Wu Su,Yin-Rong Xie,Li-Xia Wang,Ning Zhang,Yi-Long Wu,Yun Niu,Dong-Ying Zhang,Cheng-Ting Zi,Xuan-Jun Wang,Jun Sheng
Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7–12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property–activity relationship of EGCG derivatives. Compounds11and12showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC50values in the range of 22.90–37.87 μM. Compounds11and12decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds11and12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.Keywords:EGCG;synthesis;cytotoxicity;EGFR;molecular docking
研究领域:
药理学
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肿瘤学
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化学
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DOI
PubMed
高影响因子
Journal of Functional Foods
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2024
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IF 3.8
Yuan Liang,Qing Wang,Dianwen Zhang,Yiyao Gong,Qiuyan Jiang,Cong Ma,Libo Si,Tiehua Zhang,Jie Zhang,Zheng Ma
In this work, ginsenoside CK was confirmed as an EGFR tyrosine kinase inhibitor, with an IC 50 value of 32.58 ± 0.09 μM. Molecular docking showed that ginsenoside CK could fit into EGFR binding pocket, thereby acting as a ligand for EGFR. Ginsenoside CK inhibited proliferation of A549 cells as well as induced its apoptosis via downregulating anti-apoptotic factors and upregulating apoptosis induction factors. Ginsenoside CK alone and combined with gefitinib inhibited the tumor progression of A549 lung cancer xenografts in BALB/c nude mice. ELISA assay showed that ginsenoside CK combined with gefitinib alleviated the inflammatory response by suppressing the release of pro-inflammatory cytokines, indicating better inhibitory effects than ginsenoside CK or gefitinib alone. This work further confirmed that ginsenoside CK regulated the EGFR/MAPK/ERK signaling both in vitro and in vivo . In conclusion, ginsenoside CK can exhibit the anti-lung cancer effect via acting as an EGFR tyrosine kinase inhibitor.
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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DOI
高影响因子
AAPS Journal
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2017
·Vol. 19
·期 3
·814-826
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IF 3.423
Li Fengqiao,Mei Hao,Xie Xiaodong,Zhang Huijuan,Liu Jian,Lv Tingting,Nie Huifang,Gao Yu,Jia Lee
Lung cancer is the leading cancer and has the highest death rate. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has had a promising response in lung cancer therapy. Unfortunately, individuals with TKI-resistant EGFR mutations often develop acquired resistance against erlotinib. To overcome this resistance, in the present study, we developed liposomes anchored with anti-EGFR aptamer (Apt)-conjugated chitosan (Apt-Cs) as stable carriers to deliver erlotinib to the target. We loaded erlotinib into Apt-Cs-anchored liposomal complexes (Apt-CL-E) and characterized the physicochemistry of Apt-CL-E. The nanoparticles showed good biostability and a binding specificity for EGFR-mutated cancer cells guided by the Apt. The specific binding facilitated the uptake of Apt-CL-E into EGFR-mutated cancer cells. A cytotoxicity study showed an advantage of Apt-CL-E over their nontargeted liposomal counterparts in delivering erlotinib to EGFR-mutated cancer cells, resulting in cell cycle arrest and apoptosis. These results provide a good platform for future in vivo animal studies with Apt-CL-E.
研究领域:
肿瘤学
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药剂学
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分子生物学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
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2021
·Vol. 21
·期 6
·1-11
·
IF 2.447
Xiaoming Lin,Guangfei Wang,Ping Liu,Lei Han,Tong Wang,Kaili Chen,Yonglin Gao
The aim of the present study was to investigate the effects of gallic acid (GA) on the proliferation and apoptosis of colon cancer cells and to further clarify the mechanism of GA function associated with SRC and EGFR phosphorylation. HCT116 and HT29 cells were treated with different concentrations of GA for 24 h. Cell proliferation and apoptosis were analyzed using plate clone formation and flow cytometry assays, respectively. In addition, the expression of apoptosis‑related proteins was examined by western blotting. Furthermore, the level of STAT3, AKT, SRC and EGFR phosphorylation was analyzed by western blotting and immunofluorescence. Subsequently, the SRC inhibitor PP2 and the EGFR inhibitor gefitinib were used to analyze the GA‑associated mechanisms. In addition, a xenograft tumor model was established to confirm the effects of GA in vivo. The results indicated that GA inhibited cell proliferation and promoted cell apoptosis by upregulating the ratio of cleaved caspase‑3/pro‑caspase‑3 and cleaved caspase‑9/pro‑caspase‑9. Concurrently, GA decreased the level of phosphorylated (p)‑SRC, p‑EGFR, p‑AKT and p‑STAT3. Following treatment with PP2 and gefitinib in both cancer cell lines and animal model, GA was demonstrated to inhibit EGFR and SRC phosphorylation to downregulate STAT3 and AKT phosphorylation. In vivo, GA prevented tumor growth, promoted tumor apoptosis and decreased the level of p‑SRC, p‑EGFR, p‑STAT3 and p‑AKT. In conclusion, GA was indicated to suppress colon cancer proliferation by inhibiting SRC and EGFR phosphorylation.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2023
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IF 8.4
Wenjing Huang,Li Wang,Hao Zhang,Zhihao Han,Yueqing Gu
The incidence of prostate cancer has increased rapidly in recent years. And the detection of tumor markers is an effective way for early diagnosis and poor prognosis. Prostate cancer is associated with growth factor receptors. Epidermal growth factor receptor (EGFR) expression is increased in a majority of prostate cancer patients. Peptide probes have the advantages of convenient modification and selective and rapid clearance in the molecular imaging of tumors. H1 is a short peptide designed and modified based on the CDR3 region of a nanobody targeting the epidermal growth factor receptor (EGFR) with high affinity for malignant tumors that overexpress EGFR. The CDR3 sequence of nanobodies has a long finger-like structure that allows deep interaction with the cryptic epitope of the antigen. Here we synthesized a sensitive fluorescent peptide probe of H1 conjugated to imaging moieties MPA. Experimental data showed that H1-MPA targets EGFR with high affinity. Meanwhile, H1-MPA has high tumor uptake and a strong signal-to-noise ratio. In addition, the near-infrared fluorescent probe H1-MPA can determine tumor boundaries and can be used to monitor and prevent tumor metastasis, including hepatic metastasis, for accurate tumor diagnosis. H1-MPA provides a promising tool for cancer diagnosis.
研究领域:
肿瘤学
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分子生物学
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生物医学工程
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癌症诊断
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荧光成像
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DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Yan Zhang,Yuanyuan Ren,Zhen Wang,Xi Zhang,Xiaofang Li,Yi Yu,Lu Qian,Yuyan Xiong
A high-fat diet and obesity significantly increase the risk of gastric cancer (GC), with persistent obesity contributing to a notable rise in GC incidence. However, the underlying molecular mechanisms remain largely unclear. In this study, we identified exosomal SLC1A5 (Exo-SLC1A5) as a novel senescence-associated secretory phenotype (SASP) factor that promotes GC malignancy. Exosomal SLC1A5 drives GC progression by suppressing ferroptosis in a GPX4-dependent manner. Mechanistically, in the context of obesity, senescent endothelial cells release exosomal SLC1A5, which engages EGFR on GC cells, triggering SRC phosphorylation at Tyr416 and subsequent YAP1 activation at Tyr357. This leads to YAP1 interaction with MYO1B to enhance the nuclear translocation of YAP1, and subsequent upregulation of GPX4, resulting in ferroptosis suppression and accelerated GC progression. In vivo, depletion of exosomal SLC1A5 from PA-induced senescent ECs attenuated GC tumor growth and metastasis in a xenograft mouse model. These findings reveal a novel mechanism by which exosomal SLC1A5 promotes GC progression through the EGFR/SRC/YAP1/GPX4 signaling axis. Targeting the Exo-SLC1A5/EGFR/SRC/YAP1/GPX4 axis may provide a therapeutic strategy for GC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2019
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IF 3.361
Yuping Liu,Xiangliang Jiang,Yue Gu,Yan Chen
Cutaneous toxicities are the commonest side effects in patients with cancer treated using epidermal growth factor receptor inhibitors such as erlotinib . For patients with such toxicities, there is a lack of safe, effective pharmacological agents. Here we established a skin toxicity model and investigated the preventive and therapeutic effect of Diallyl Trisulfide (DATS) in vivo. The mouse skin toxicities model was established through continuous administration of erlotinib for 49 days. Meanwhile, the mice in the experimental group underwent DATS treatment for 49 days. Hematoxylin and eosin (HE) staining and oil red O staining of back and limb skin was performed to determine whether DATS aqueous extract can reverse the skin toxicities caused by erlotinib. Compared with the erlotinib group, the incidence of rash in the DATS group was lower. In addition, in the DATS group, the degree of skin redness and herpes was mild, the body weight was stable, and the activity was favorable. By comparing the HE and oil red O staining results for the mouse skin, the degree of keratin hyperplasia was determined to be lower in the experimental group than in the erlotinib group, and the number of purulent neutrophils decreased. The number of follicles was relatively less. The release of TNF-α, IL-6 and other inflammatory factors was reduced by DATS. Erlotinib hydrochloride can cause severe skin toxicities, and DATS prevents skin toxicities, its mechanism may be related to DATS reduced erlotinib-induced inflammatory injury .
研究领域:
肿瘤学
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药理学
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毒理学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2017
·Vol. 16
·期 6
·9401-9408
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IF 1.692
Yao‑Dong Chen,Yu Zhang,Tian‑Xiu Dong,Yu‑Tong Xu,Wei Zhang,Ting‑Ting An,Peng‑Fei Liu,Xiu‑Hua Yang
Malignant gliomas are a group of aggressive neoplasms among human cancers. The curative effects of current treatments are finite for improving the prognosis of patients. Hyperthermia (HT) is an effective treatment for cancers; however, the effects of HT with different temperatures in treatment of MG and relevant mechanisms remain unclear. MTT assay and Annexin V‑fluorescein isothiocyanate/propidium iodide staining were used for investigating the proliferation and apoptosis of C6 cells, respectively. Western blotting was applied to detect the expression of proteins. Ultrasonography was employed to evaluate the tumor formation rate, growth rate, angiogenesis rate and degree of hardness of tumors in vivo. The authors certified that HT with 42‑46˚C x 1 h, 1 t could inhibit proliferation, promote apoptosis, reduce tumor formation rate, growth rate, angiogenesis rate, degree of hardness of tumors, ischemic tolerance and anoxic tolerance, and have synergy with temozolomide in C6 cells. Long‑term HT (43˚C x 1 h, 1 t/5 d, 90 d) did not cut down the sensitivity of C6 cells to HT, and sustainably inhibited the proliferation of C6 cells. Furthermore, the authors proved HT produced these effects primarily through inhibition of the EGFR/STAT3/HIF‑1A/VEGF‑A pathway.
研究领域:
肿瘤学
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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
ANALYTICA CHIMICA ACTA
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2023
·
IF 6.2
Xuegang Li,Pengqi Gong,Xue Zhou,Shankun Wang,Yingxuan Liu,Yanan Zhang,Linh V. Nguyen,Stephen C. Warren-Smith,Yong Zhao
An advanced multi-parameter optical fiber sensing technology for EGFR gene detection based on DNA hybridization technology is demonstrated in this paper. For traditional DNA hybridization detection methods, temperature and pH compensation can not be realized or need multiple sensor probes. However, the multi-parameter detection technology we proposed can simultaneously detect complementary DNA, temperature and pH based on a single optical fiber probe. In this scheme, three optical signals including dual surface plasmon resonance signal (SPR) and Mach-Zehnder interference signal (MZI) are excited by binding the probe DNA sequence and pH-sensitive material with the optical fiber sensor. The paper proposes the first research to achieve simultaneous excitation of dual SPR signal and Mach-Zehnder interference signal in a single fiber and used for three-parameter detection. Three optical signals have different sensitivities to the three variables. From a mathematical point of view, the unique solutions of exon-20 concentration, temperature and pH can be obtained by analyzing the three optical signals. The experimental results show that the exon-20 sensitivity of the sensor can reach 0.07 nm nM −1 , and the limit of detection is 3.27 nM. The designed sensor gives a fast response, high sensitivity, and low detection limit, which is important for the field of DNA hybridization research and for solving the problems of biosensor susceptibility to temperature and pH.
研究领域:
生物医学工程
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Yancen Li,Chengyu Wan,Fan Li,Guang Xin,Tao Wang,Qilong Zhou,Tingyu Wen,Shiyi Li,Xiaoting Chen,Wen Huang
Background: Isatidis Folium, a botanical drug widely used in traditional medicine, is known for its anti-inflammatory properties, including heat-clearing, detoxifying, and blood-cooling effects. Although its potential in sepsis treatment has been suggested, the bioactive metabolites and underlying mechanisms remain poorly understood.Methods: Network pharmacology and molecular docking were employed to identify the therapeutic effects and mechanisms of Indirubin, the major bioactive metabolite of Isatidis Folium, in sepsis treatment. In vivo, a cecal ligation and puncture (CLP)-induced mouse sepsis model was used to evaluate the protective effects of Indirubin through histopathological analysis, ELISA, and biochemical assays. In vitro, RAW264.7 cells were stimulated with LPS and treated with varying concentrations of Indirubin. The anti-inflammatory effects of Indirubin were assessed using ELISA, apoptosis assays, and Western blotting.Results: Network pharmacology analysis identified Indirubin as the major bioactive metabolite of Isatidis Folium and EGFR and SRC as its key molecular targets. Experimental validation demonstrated that Indirubin significantly improved survival rates, alleviated tissue injury, and suppressed inflammatory responses in sepsis models. Mechanistically, Indirubin inhibited LPS-induced activation of the EGFR/SRC/PI3K and NF-κB/MAPK pathways in macrophages, significantly reducing cell death and inflammation in RAW264.7 cells.Conclusion: Indirubin, the primary bioactive metabolite of Isatidis Folium, exerts protective effects against sepsis by targeting the EGFR/SRC/PI3K and NF-κB/MAPK signaling pathways in macrophages. These findings provide a mechanistic basis for the development of Indirubin as a multi-target therapeutic agent for sepsis treatment.
研究领域:
药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-15
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IF 3.9
Xia Hong,Tai Xue-jiao,Cheng Wang,Wu Yi,He Dan,Wang Li-feng,Liu Hao,Zhang Shen-yi,Sun Yu-ting,Liu Hang-zhi,Liu Dan-dan,Zhao Hu-zi,Ji Fu-yun,Li Xi-hua
Small cell lung cancer (SCLC) is a therapeutically challenging disease. Metformin, an effective agent for the treatment of type 2 diabetes, has been shown to have antitumour effects on many cancers, including non-small cell lung cancer (NSCLC) and breast cancer. Currently, the antitumour effects of metformin on SCLC and the underlying molecular mechanisms remain unclear. CCK-8, EdU, colony formation, flow cytometry, immunofluorescence, molecular docking, western blotting, nude mouse transplanted tumour model, and immunohistochemistry experiments were conducted to analyse gene functions and the underlying mechanism involved. In vitro experiments demonstrated that metformin inhibited the growth of SCLC cells (H446, H526, H446/DDP and H526/DDP), which was confirmed in xenograft mouse models in vivo. Additionally, metformin induced cell cycle arrest, apoptosis, and autophagy in these SCLC cells. The molecular docking results indicated that metformin has a certain binding affinity for EGFR. The western blotting results revealed that metformin decreased the expression of EGFR, p-EGFR, AKT, and p-AKT, which could be reversed by EGF and SC79. Moreover, metformin activated AMPK and inactivated mTOR, and compound C and SC79 increased the levels of p-mTOR. Metformin can not only enhance the antitumour effect of cisplatin but also alleviate the toxic effects of cisplatin on the organs of xenograft model animals. In summary, the current study revealed that metformin inhibits the growth of SCLC by inducing autophagy and apoptosis via suppression of the EGFR/AKT/AMPK/mTOR pathway. Metformin might be a promising candidate drug for combination therapy of SCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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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）