INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2020
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IF 4.845
Dianlong Jia,Yujiao Yang,Fengjiao Yuan,Qing Fan,Feifei Wang,Yujiao Huang,Hao Song,Ping Hu,Rui Wang,Guangyong Li,Renmin Liu,Jun Li
Epidermal growth factor receptor (EGFR) is overexpressed in a wide range of solid tumors . In this study, we exploited a high-affinity EGFR-antagonistic affibody (Z EGFR ) coupled to a doxorubicin loaded pegylated liposome (LS-Dox) for concurrent passive and active targeting of EGFR + A431 tumor cells in vitro and in vivo . The in vitro studies revealed that the Dox liposomes coupled with Z EGFR (AS-Dox) showed a higher Dox uptake than LS-Dox in EGFR + A431 cells but not in EGFR − B16F10 cells, resulting in a selectively enhanced cytotoxicity. In vivo , AS-Dox confirmed its long circulation time and efficient accumulation in tumors. This targeted chemotherapy achieved greater tumor suppression. Further, this low-dose but effective targeted treatment reduced systemic toxicity such as body weight loss and organ injury demonstrated by H&E staining. Thus, selective targeting of LS-Dox coupled with Z EGFR enhanced antitumor effects and improved systemic safety. These results demonstrated that LS-Dox coupled with Z EGFR might be developed as a potential tool for therapy of EGFR + tumors.
研究领域:
肿瘤学
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药学
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分子生物学
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DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
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2020
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IF 5.88
Jun Tang,Fushuang Zheng,Jungang Zhao,Jianzhu Zhao
The aim of this study was to prepare a promising drug carrier for treatment of lung cancer. The self-assembly nanoparticles of SDP-GEM/PEI-PEG-anti-EGFR with chemotherapeutic drug of gemcitabine (GEM), Magnetic resonance imaging (MRI) guided- imaging and targeting of anti- Epidermal Growth Factor Receptor (anti-EGFR) were designed. The imaging capacity, targeting feasibility and anti-tumor function were evaluated respectively. SDP-GEM/PEI-PEG-anti-EGFR exhibited contrast enhancement under T2 Weight Image (T2WI) and a liner relationship was found between the concentration and relaxation rate of R2 and R2* in vitro . With the targeting of anti-EGFR, the endocytosis of nanoparticles increased significantly, which effectively killed lung cancer cells in vitro , and importantly it can be accurately delivered to tumor site within 3 h in vivo . Prolonged lifetime and smaller tumor volume demonstrated that SDP-GEM/PEI-PEG-anti-EGFR efficiently inhibited tumor growth in vivo . Therefore, SDP-GEM/PEI-PEG-anti-EGFR was an effective and safe drug carrier, which had a great potential application in MRI-guided lung cancer therapy.
研究领域:
纳米技术
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癌症治疗
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分子影像
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药物递送系统
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2026
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IF 7.8
Fang Lei,Wu Yue,Wang Jiarui,Wu Yu,Ma Junhui,Li Xiuju,Deng Wei,Ma Haixia,Li Yulong,Xiang Guangya,Ma Xiang
Proteolysis targeting chimeras (PROTACs) have been utilized to overcome drug resistance by degrading mutant EGFR in non-small cell lung cancer (NSCLC) therapy. However, their therapeutic efficacy is often compromised by the complex tumor microenvironment, which can lead to the reduced sensitivity of lung cancer cells to PROTACs. In this study, oxygen supplier (CaO 2 ) and PROTAC co-loaded liposomes (LCP) are developed for simultaneously promoting EGFR degradation and hypoxic microenvironment alleviation. Calcium peroxide (CaO 2 ) can release oxygen to modulate the hypoxic microenvironment, thereby reducing HIF-1α expression and enhancing the sensitivity of lung cancer cells. Compared with PROTACs administered alone, LCP exhibited enhanced tumor cell killing effect, improved protein degradation capacity, and superior tumor growth inhibition in NSCLC animal models. Mechanistic analysis reveals that LCP modulates hypoxia-associated proteins, including FGFR1, ERK, and TGF-α, contributing to the enhanced therapeutic efficacy. The LCP developed herein offers a strategy for enhancing NSCLC therapy by remodeling the hypoxic tumor microenvironment.
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2026
·
IF 5.1
Zhongquan Song,Yanmei Zhu,Surong Fang,Shuhua Han
Aims The EGFR-C797S mutation is the main cause of Osimertinib resistance. No effective treatment regimen is currently available for patients harboring EGFR-activation mutation/T790M/cis-C797S triple mutations. Materials and methods Nine patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activation mutation/T790M/cis-C797S mutation were investigated. After Osimertinib resistance, these patients were treated with Endostar combination with Osimertinib. Network pharmacology and molecular dynamics simulations were used to clarify active sites of Endostar and the effect on protein conformation. In vivo and in vitro , EGFR L858R-T790M-C797S/H1975 cells were used to investigate the efficacy of co-treatment. Key findings Two patients achieved partial response (PR), six achieved stable disease (SD) and one had progressive disease (PD) at the 6-month efficacy assessment of co-treatment, resulting in an objective response rate (ORR) of 66.7% and a disease control rate (DCR) of 88.9%. These patients achieved a median progression-free survival (PFS) of 8.9 months and a median overall survival (OS) of 18.5 months, and no patients experienced grade III or IV adverse events. Endostatin, the active ingredient of Endostar, bound EGFR to “pseudo” mediate EGFR signaling pathway, and the introduction of Endostar enhanced the binding of Osimertinib to EGFR L858R/T790M/C797S protein. In vitro and in vivo experiments have found the co-treatment restored sensitivity to Osimertinib. Moreover, the combination therapy significantly inhibited the activation of the EGFR signaling pathway and tumor neovascularization. Significance This work demonstrated for the first time that Endostar enhanced the antitumor efficacy of Osimertinib, offering a potential therapeutic approach for patients harboring triple mutations.
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2017
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IF 2.93
Hongying Gao,Zimo Yang,Xinglin Yang,Yu Rao
Osimertinib has been identified as a promising therapeutic drug targeting for EGFR T790M mutant non-small cell lung cancer (NSCLC). A new series of N -oxidized and fluorinated osimertinib derivatives were designed and synthesized. The cellular anti-proliferative activity, kinase inhibitory activity and the activation of EGFR signaling pathways of 1 – 6 in vitro were determined against L858R/T790M and wild-type EGFR, the antitumor efficacy in NCI-H1975 xenografts in vivo were further studied. Compound 2 , the newly synthesized N -oxide metabolite in N , N , N ′-trimethylethylenediamine side chain of osimertinib, showed a comparable kinase selectivity in vitro and a slightly better antitumor efficacy in vivo to osimertinib, making it valuable and suitable for the potential lung cancer therapy.
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DOI
PubMed
高影响因子
Current Molecular Pharmacology
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2023
·Vol. 16
·期 7
·712-724
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IF 2.7
Song Jin,Xu Xiaolong,He Shasha,Wang Ning,Bai Yunjing,Chen Zhaoxia,Li Bo,Zhang Shengsheng
Background: Myristicin is a type of natural compound showing anti-proliferative, anti-microbial, and anti-inflammatory effects. However, its role in gastric cancer treatment remains unknown. Objective: In this study, the effect of myristicin on gastric cancer as well as its underlying
mechanism was investigated. Methods: Human gastric cancer cells were exposed to various concentrations of myristicin (0, 7.8125, 15.625, and 31.25 μM) for 48 h. Then CCK-8, fluorescence-activated cell sorting, and Hoechst staining were performed to evaluate the cell proliferation and
apoptosis. The levels of proteins associated with cell cycle, apoptosis, endoplasmic reticulum (ER) stress, and EGFR/ERK signaling pathway were detected by western blot. JC-1 staining was conducted to determine the mitochondrial membrane potential. On the other hand, the effect of myristicin
on gastric cancer growth and apoptosis was also determined in vivo. Results: Myristicin retarded proliferation and induced ER stress and apoptosis in gastric cancer cells, with decreased expression of cyclins, increased Bax expression, activated caspases, and enhanced cytochrome C release
and mitochondrial ROS. Furthermore, the EGFR/ERK signaling pathway was restrained by myristicin. In addition, EGFR over-expression abolished the inhibitory function of myristicin on proliferation, apoptosis, and ER stress. Also, myristicin inhibited the growth of gastric cancer cells as well
as the EGFR/ERK signaling pathway in vivo. Conclusion: Myristicin exerts an anti-cancer effect on gastric cancer cells by restraining the EGFR/ ERK signaling pathway. It may have the potential to be applied as a novel drug in gastric cancer treatment.
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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DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
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2025
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IF 4.3
Qiang Pang,Shansong Huang,Xiaodong Li,Jiaqing Cao
Background: The high morbidity and mortality rates of colorectal cancer (CRC) have been a public health concern globally, and the search for additional therapeutic options is imminent. Hyodeoxycholic acid (HDCA) has been receiving attention in recent years and has demonstrated potent efficacy in several diseases. Nonetheless, the antitumor effects and molecular pathways of HDCA in CRC remain largely unexplored.Methods: In this study, we investigated how HDCA influences the growth potential of CRC cells using techniques such as flow cytometry, Edu assay, CCK-8, colony formation assay, Western blot analysis, and animal experiments.Results: It was found that HDCA treatment of CRC cells was able to significantly inhibit the proliferative capacity of the cells. Furthermore, it was discovered that HDCA primarily stimulated Farnesoid X Receptor (FXR) rather than Takeda G protein coupled receptor 5 (TGR5) to suppress CRC growth. It was also confirmed that HDCA inhibited the Epiregulin (EREG)/Epidermal Growth Factor Receptor (EGFR) pathway by activating FXR, and a negative correlation between FXR and EREG was analyzed in CRC tissue samples. Finally, in vivo animal studies confirmed that HDCA inhibited CRC proliferation without hepatotoxicity.Conclusion: Our findings indicate that HDCA suppresses the EREG/EGFR signaling route by activating FXR, thereby hindering the growth of CRC cells and demonstrating a tumor-inhibiting effect in CRC. This study may provide a new therapeutic strategy to improve the prognosis of CRC.
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
APOPTOSIS
·
2026
·Vol. 31
·期 6
·158
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IF 9
Zhen Shuman,Gao Yifan,Wang Jiaqi,Ren Jingyi,Pei Huanting,Yin Danjing,Deng Yandong
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remains a major clinical challenge in non-small cell lung cancer. Emerging evidence indicates that metabolic reprogramming and epigenetic alterations contribute to drug resistance, particularly through the evasion of ferroptosis, a regulated form of cell death characterised by lipid peroxidation. This study investigated the role of lactate-associated histone modifications in driving EGFR-TKI resistance. Resistant lung adenocarcinoma tissues and cell lines were analysed using transcriptomics, Cleavage Under Targets and Tagmentation (CUT&Tag) profiling, and biochemical assays. Glycolytic activity, lactate accumulation, and ferroptosis-related lipid peroxidation were assessed, followed by genetic and pharmacological interventions and in vivo xenograft validation. Resistant cells exhibited enhanced glycolysis and lactate accumulation, with pathway analyses highlighting ferroptosis evasion as a key resistance-associated process. Consequently, histone H4 lysine 8 lactylation (H4K8la) was significantly elevated in resistant tissues and cells. Mechanistically, H4K8la was enriched at transcription start sites, particularly at the promoter of aldo-keto reductase family 1 member C1 (AKR1C1). This epigenetic modification profoundly suppressed ferroptosis and promoted drug resistance. Disrupting this H4K8la-AKR1C1 defence axis restored lipid peroxidation, increased ferroptotic sensitivity, and resensitised resistant cells to EGFR-TKIs, as confirmed in vivo. These findings reveal a novel lactate-driven epigenetic mechanism that orchestrates ferroptosis escape and EGFR-TKI resistance, offering a promising therapeutic strategy to overcome treatment failure.
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DOI
PubMed
高影响因子
JOURNAL OF CELL BIOLOGY
·
2025
·Vol. 225
·期 1
·e202501091
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IF 6.4
Gao Kun,Shi Ruiya,Xu Chenying,Mao Zhaoyang,Guo Changying,Jin Liang
DNA damage repair is vital for maintaining genetic stability and integrity of cells that encounter DNA-damaging agents. So far, a series of multifunctional proteins and long noncoding RNAs (lncRNAs) have been demonstrated to participate in the DNA damage response (DDR). However, our current understanding of detailed mechanisms of DNA damage repair remains limited. Herein, we report that lncRNA EGFR-AS1 is functionally involved in DDR in both non–small-cell lung cancer cells and noncancerous cells. Using DNA repair reporter, we found that EGFR-AS1 overexpression significantly enhances the efficiency of both the classical nonhomologous end-joining and homologous recombination pathways. Through the lncRNA interactome, we identified a set of DNA repair factors, including the canonical DNA damage sensor PARP1 and NAD+ supplier NMNAT1. Upon DNA damage, DNA-activated PARP1 binds to EGFR-AS1 and forms a ternary complex with NMNAT1, promoting NAD+ utilization and poly(ADP-ribosyl)ation (PARylation) of PARP1. Additionally, EGFR-AS1 also facilitates displacing PARP1 from the sites of damaged DNA. Our findings demonstrate a lncRNA-associated PARP1 activation and displacement in DDR and highlight the potential of EGFR-AS1 as a target for cancer therapy.
研究领域:
分子生物学
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肿瘤学
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遗传学
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细胞生物学
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转化医学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
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2025
·Vol. 15
·期 29
·23136-23145
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IF 4.6
Zhenbin Xu,Hongpeng Duan,Yuling Shi,Zixia Zhou,Zhuo Wei,Xuechen Qian,Jian Lu,Yuemingming Jiang,Feng Mao,Nianyu Xue,Shengmin Zhang
Paclitaxel (PTX)-loaded nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) represent a promising platform for improving chemotherapeutic efficacy in triple-negative breast cancer (TNBC), a highly aggressive subtype with limited therapeutic targets and poor clinical outcomes. To address challenges of nonspecific distribution and systemic toxicity associated with conventional PTX treatment, we designed a multifunctional nanocarrier system integrating active targeting and ultrasound responsiveness. The nanoparticles (PTX@TNPs) were prepared using a double emulsion method, encapsulating PTX and perfluoropentane (PFP) in a PLGA matrix, followed by surface conjugation of GE11 peptides targeting the epidermal growth factor receptor (EGFR) via EDC/NHS chemistry. Comprehensive physicochemical characterization revealed favorable particle size, colloidal stability, and drug loading efficiency. In vitro studies using EGFR-overexpressing MDA-MB-231 cells demonstrated significantly enhanced cellular uptake and cytotoxicity of PTX@TNPs, especially under ultrasound irradiation. In vivo, PTX@TNPs combined with ultrasound markedly inhibited tumor growth, suppressed microvessel density, and induced apoptosis in a TNBC xenograft model, while exhibiting reduced systemic toxicity compared to free PTX. Histological and immunohistochemical staining confirmed downregulation of proliferation marker Ki-67 and angiogenesis marker CD31 in tumor tissues following treatment. These findings highlight the synergistic therapeutic potential of combining EGFR-mediated active targeting with ultrasound-triggered drug release and underscore the translational value of PTX@TNPs as a safe and efficient nanoplatform for TNBC treatment.
研究领域:
药理学
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肿瘤学
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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
Oncotarget
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2017
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IF 5.168
Jingwei Shao,Guirong Zheng,Hongning Chen,Jian Liu,Aixiao Xu,Fan Chen,Tao Li,Yusheng Lu,Jianguo Xu,Ning Zheng,Lee Jia
Therapies targeting epidermal growth factor receptor (EGFR) can effectively treat with non-small cell lung cancer (NSCLC), but NSCLC’s drug resistance makes it intractable. Herein, we showed that RU486 metabolite metapristone inhibited the proliferation of various NSCLC cell lines with either wild (A549, H1299, H520) or mutated EGFR (H1975, HCC827). The suppression was resulted from inhibition by metapristone of EGFR signaling pathways through down-regulating the EGFR, PTEN, as well as AKT and ERK proteins. In addition, metapristone inhibited anti-apoptotic marker Bcl-2, and activated pro-apoptotic key signaling proteins caspase-3, and poly (ADP-ribose) polymerase. Metapristone induced A549 and H1975 cell cycle via arrest at the G0-G1 stage. What’s more, metapristone inhibited the growth of NSCLC xenografts in BALB/c nude mice through decreasing the expression of tumor growth biomarkers PCNA and EGFR. Taken together, the present study demonstrated that metapristone suppressed NSCLC proliferation by promoting apoptosis via decrease the cellular EGFR-mediated PI3K/AKT pathways. The results suggest metapristone a new treatment for EGFR-overexpressed NSCLC.
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
JOURNAL OF CHEMICAL RESEARCH
·
2015
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IF 0.633
Haidong Liu,Yongfeng Lv,Yuan Li,Jin Cai,Junqing Chen,Yu Qin,Min Ji
A convenient route for the synthesis of a third-generation epidermal growth factor receptor inhibitor, mereletinib (AZD9291) using starting materials that are commercially available has been achieved through reactions that are readily conducted under mild conditions. Importantly, a 5 g scale synthesis was also accomplished and this method could therefore be useful in the synthesis of similar drugs.
研究领域:
药物化学
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有机合成
·
肿瘤学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）