iScience
·
2025
·
IF 4.1
Weiyu Wu,Ren Zhang,Geer Chen,Ziyu Chen,Zicong Lin,Yin Chen,Jiaqi Li,Weilin Liao,Junyi Wang,Xiaoxuan Wang,Junhao Huang,Lijuan Ma,Haijie Yu
Natural compounds are valuable templates for anticancer drug development. Through high-throughput screening of 1,880 natural compounds and structure-activity analysis, we identified sappanchalcone (SC) as a potent agent that induces intracellular calcium elevation and causes G2/M phase arrest in H1975, H1299, and A549 cells. Transcriptomic and protein-protein interaction network analyses revealed multi-target effects of SC, involving oxidative stress, cell cycle dysregulation, and ion homeostasis perturbation. Mechanistically, SC induced ROS accumulation, upregulated the DNA damage, and enhanced the expression of p21 and GADD45α, thereby suppressing the CDK1/Cyclin B1 complex. SC also activated ER stress pathways by phosphorylating IRE1α and PERK. Notably, SC downregulated the mechanosensitive ion channel PIEZO1, and its inhibitor ruthenium red (RR) significantly reversed SC-induced proliferation inhibition and G2/M arrest. This study delineates an antitumor mechanism of SC mediated via a calcium–ER stress–cell cycle axis with translational potential for NSCLC therapy.
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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天然产物化学
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细胞信号传导
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-19
·
IF 10.2
Chen Bing,Zheng Kaifan,Fang Shubin,Huang Kangping,Chu Chengchao,Zhuang Junyang,Lin Jin,Li Shaoguang,Yao Hong,Liu Ailin,Liu Gang,Lin Jizhen,Lin Xinhua
Background The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC). Results In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts. Conclusion This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.
研究领域:
癌症治疗
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纳米医学
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药物递送系统
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免疫学
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生物偶联化学
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DOI
高影响因子
Antioxidants
·
2025
·Vol. 14
·期 10
·1222
·
IF 6.6
Hanziyi Zhou,Shibo Sun,Haowen Liu,Tong Li,Yiran Xu,Rui Yang,Haiyan Liu,Leiyu He,Weiping Xu,Shui Guan,Jianqiang Xu
Selenoprotein thioredoxin reductase 1 (TXNRD1) is frequently upregulated in various cancer cells to sustain cellular redox homeostasis, and its inhibition has emerged as a promising anti-cancer strategy. In this study, we identified PK11007, a thiol-modifying compound previously characterized as a p53 reactivator, as a potent inhibitor of TXNRD1. PK11007 irreversibly inhibited recombinant TXNRD1 in a time- and dose-dependent manner. Using differential scanning fluorimetry (DSF) and LC–MS/MS analysis, we confirmed that PK11007 covalently modifies the C-terminal redox motif (Cys497-Sec498) of TXNRD1. In non-small cell lung cancer (NSCLC) H1299 cells, PK11007-induced TXNRD1 inhibition disrupted cellular redox balance, leading to impaired autophagy flux and cell death. Similar autophagy suppression was observed in TXNRD1-knockdown cells, as well as pharmacological inhibition of TXNRD1 by Auranofin (AF) and TXNRD1 inhibitor 1 (TRi-1). Taken together, these findings highlight that oxidative stress contributes to the cytotoxic effects of PK11007 and uncover autophagy disorder as a downstream consequence of TXNRD1 inhibition.
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PubMed
高影响因子
MICROCHEMICAL JOURNAL
·
2025
·
IF 5.1
Xiaohui An,Ze Zhang,Hehua Zhang,Xin Xu,Tong Shen,Yuting Zhang,Xiaoyi Yang,Yiyang Fan,Hongzhi Pan,Dong Chang
Early diagnosis and treatment can significantly enhance the prognosis of patients with non-small cell lung cancer (NSCLC); however, current diagnostic methods remain plagued by inadequate sensitivity or excessive invasiveness. This study describes the innovative construction of a dual-fluorescence, dual-target biosensor based on copper nanoclusters (CuNCs) and hollow mesoporous silica nanospheres (HMSNs) for highly sensitive detection of CD91 and CD151 on the surface of NSCLC exosomes. Specifically, HMSNs regulate the fluorescence signals of red and blue glutathione-CuNCs by loading Ce 3+ and Fe 3+ and conjugating a pH-responsive chitosan coating: Ce 3+ significantly enhances the fluorescence signal of red CuNCs by inducing their aggregation, whereas Fe 3+ quenches the fluorescence signal of blue CuNCs through oxidation. Exosomes are captured using a CD63 aptamer conjugated to streptavidin magnetic beads. HMSN-Ce 3+ -CS-antiCD151 and HMSN-Fe 3+ -CS-antiCD91 probes are then employed to target exosome surface proteins CD151 and CD91, respectively, allowing synchronous detection of dual-fluorescence and dual targets. We then measured and analyzed the change ratio of fluorescence signals, and optimized the detection parameters while evaluating the sensitivity, stability, and linear range of the system. The detection limits of red and blue fluorescence systems were 1058 particles·mL −1 and 239 particles·mL −1 , and ranges of linearity were 4 × 10 3 –4 × 10 8 particles·mL −1 and 7 × 10 2 –7 × 10 6 particles·mL −1 , respectively. Overall, this study introduces a novel strategy for the early screening of NSCLC, with high sensitivity and minimal invasiveness. The complementary design of the dual-fluorescence system extends its detection range and holds potential for clinical application.
研究领域:
生物传感器
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纳米技术
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癌症诊断
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生物化学
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材料科学
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DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-11
·
IF 10.6
Liu Jie,Liu Chengxiang,Tang Jinghua,Chen Qiao,Yu Yan,Dong Yan,Hao Jie,Wu Wei
Radiotherapy (RT) is one of the important treatment modalities for non-small cell lung cancer (NSCLC). However, the maximum radiation dose that NSCLC patient can receive varies little. Therefore, the exploitation of novel RT sensitization approaches is a critical need for the clinical treatment. RT resistance in NSCLC is linked to tumor microenvironment (TME) hypoxia, cell cycle arrest and associated genetic alterations. Here, we designed a novel method for targeted delivery of quercetin (QT) and CeO2 to enhance RT sensitivity. We loaded QT into CeO2@ZIF-8-HA nanoparticles to prevent its degradation in the circulatory system and successfully delivered QT and CeO2 targeted to NSCLC tumors. Under the protection and targeted delivery of Zeolitic Imidazolate Framework-8 (ZIF-8), the nanocomplexes exhibited excellent catalytic mimetic activity in decomposing H2O2 into O2, thus significantly reversing the hypoxia of TME, while the radiosensitizer QT caused DNA damage directly after RT. In a subcutaneous tumor model, CeO2@ZIF-8-HA overcame radiation resistance and enhanced therapeutic efficacy. This multiple sensitization strategy combining delivery of QT and CeO2@ZIF-8-HA nanozymes opens a promising approach for RT of NSCLC.
研究领域:
肿瘤学
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纳米技术
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放射肿瘤学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NATURAL PRODUCTS
·
2023
·
IF 5.1
Hongyan Lin,Dongxuan Ai,Qingqing Liu,Xinling Wang,Jiale Gao,Qingqing Chen,Lingyu Ruan,Yuheng Tao,Jian Gao,Liqun Wang
Cancer is a major disease threatening human health worldwide, among which non-small-cell lung cancer (NSCLC) is the most deadly. Clinically, almost all anticancer drugs eventually fail to consistently benefit patients due to serious drug resistance. AKT is a key effector of the PI3K/AKT/mTOR pathway, which is closely related to the occurrence, development, and drug resistance of tumors. Herein, we first designed and synthesized 20 kinds of novel hybrid molecules targeting both tubulin and AKT based on a podophyllotoxin (PPT) skeleton through computer-aided drug design. By CCK8 assay, we screened the compound D1-1 (IC50 = 0.10 μM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC50 = 12.56 μM) and 300 times higher than gefitinib (IC50 = 32.15 μM). Affinity analysis results showed that D1-1 not only retained the tubulin targeting of PPT but also showed strong AKT targeting. Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.
研究领域:
肿瘤学
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药理学
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药物设计
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癌症生物学
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分子生物学
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DOI
PubMed
高影响因子
Food Bioscience
·
2021
·
IF 4.24
Yonglu Li,Yiru Zhang,Yaxuan Wang,Xin Yu,Ting Yu,Xiaodong Zheng,Qiang Chu
With high morbidity and mortality, non-small cell lung cancer (NSCLC) has become a challenge for humans, because its clinic chemotherapies still remain unsatisfactory. In this study, the leaf part of a traditional Chinese plant, Tetrastigma hemsleyanum (TL), was studied, and its main flavones compounds were extracted and purified (TLF), which were composed of 5-caffeoylquinic acid, 3-caffeoylquinic acid, 4-caffeoylquinic acid, quercetin-3-O-rutinoside and kaempferol-3-O-rutinoside. To study the anti-NSCLC ability of TLF, in vitro and in vivo studies were done. TLF inhibited the proliferation and migration of A549 cells and caused mitochondrial dysfunction. TLF significantly suppressed the tumor weight and volume, and down-regulated Ki67, proliferation cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) productions. To determine the intrinsic mechanism, proteins alternations were measured in solid tumors, and results showed that TLF blocked the Akt/mTOR pathway, and thereby induced autophagy, triggering Bcl and Caspase-dependent pathways, resulting in A549 cells’ apoptosis. This study indicated that TLF is a potential candidate to be an anti-NSCLC drug, or a supplementary resource for chemotherapy.
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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中医药学
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DOI
高影响因子
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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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Li Gao,Li-Hua Yang,Fang-Cheng Jiang,Wang-Yang Ye,Xin Chen,Zhao-Ji Liu,Rong-Quan He,Wan-Ying Huang,Zhen-Bo Feng,Jin-Liang Kong,Ze-Feng Lai,Gang Chen
Background Although immune checkpoint blocking (ICB) therapeutic agents have significantly improved the survival for many cancer patients, the efficacy of ICB therapy for non-small cell lung cancer (NSCLC) patients remains limited. Combining ICB therapy with other strategies that is able to stimulate tumor immunogenicity or increase infiltration of T cells aroused great concern in cancer therapy.Results Herein, we constructed a kind of AuNP@NH2-PEG-SH/PD-L1 siRNA nanoparticle complex which showed prominent photothermal therapeutic (PTT) effects triggered by NIR laser and could efficiently deliver PD-L1 siRNA into NSCLC cells (knock-down efficiency were 75.8% and 83% in HCC827 and A549 cells). During the process of photothermal stimulation, discrepancies in heat shock protein expression were observed in NSCLC cells. Knocking down PD-L1 expression in NSCLC cells such as A549 and HCC827 cells activated the co-culturing Jurkat cells and enhanced their tumor-killing effect in vitro (cell inhibition rate was 62.65% for HCC827 cells and 57.03% for A549 cells). The gold nanoparticle complexes exhibited remarkable PTT effect for the engrafted NSCLC cells in zebrafish larvas. Furthermore, the nano complexes could promote the activation of the xenografted human peripheral blood mononuclear cells (PBMCs) and enhance the killing of the NSCLC cells in the larvas.Conclusion It is well known that gold nanoparticle is one of the several metal nanoparticles approved for clinical trial by American FDA. This work has demonstrated the outstanding PTT and immunotherapeutic effects of gold nanoparticle complexes on NSCLC, indicating great potential in clinical regiment of lung cancers.
研究领域:
肿瘤学
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免疫学
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生物医学工程
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Jianchao Zhang,Xiao Chen,Congli Chen,Fengming Li,Xiaoxiao Song,Chaowei Liu,Kefan Liao,Ming-Yuan Su,Chris Soon Heng Tan,Lijing Fang,Hai Rao
Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acids─Gly, Pro, and Lys─as the ligand to recruit the corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs, to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC. We found that the extent of EML4-ALK and EGFR reduction can be easily fine-tuned by using different degradation signals. These amino acid-based PROTACs, termed AATacs, hindered proliferation and induced cell cycle arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs, AATacs are small, interchangeable but with different degradation efficiency. Our study further expands the repertoire of E3 ligases and their ligands for PROTAC application, improving the versatility and utility of targeted protein degradation for therapeutic purposes.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 66
·38298-38308
·
IF 3.049
Xiaojun Xu,Shu Xing,Mengjia Xu,Pan Fu,Tingting Gao,Xiaokang Zhang,Yang Zhao,Chao Zhao
Screening epidermal growth factor receptor (EGFR) mutations, especially deletions, is essential for diagnosis of non-small cell lung cancer (NSCLC) and also critical to inform treatment decisions for NSCLC patients. Here, we demonstrated a facile peptide nucleic acid (PNA) microarray-based fluorometric method for sensitive and specific detection of EGFR mutation, using rolling circle amplification (RCA), graphene oxide (GO), and a fluorescently-labeled detection probe (F-DP). First, the EGFR gene sequence was efficiently captured by the label-free PNA probe which was attached on the surface of a 96-well plate. And then, the EGFR mutation sequence was specifically amplified by RCA using the circular DNA, which was formed by the ligation of the padlock probe when hybridizing with the EGFR mutation, as a template. The single-stranded RCA product (RCAP) was then sensitively detected with the F-DP and GO system. This method has a detection limit of 0.3 pM for EGFR mutation and a high discrimination capability to target EGFR mutation against EGFR wildtype. The use of a PNA microarray and a fluorescence quenching platform make this system quite suitable for high-throughput analysis of EGFR mutations in resource-limited settings without the need of costly and cumbersome equipment. Furthermore, this detection system provides a novel way for the diagnosis of other diseases that are caused by gene deletion mutations.
研究领域:
分子生物学
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癌症诊断
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2026
·
IF 5.9
Minzhang Guo,Lei Xue,Jun Li,Mengni Zhu,Hang Long,Jiangzhou Peng
Non-small cell lung cancer (NSCLC) poses a formidable therapeutic challenge due to drug resistance and limited treatment efficacy. To address this, we developed a novel nanodrug delivery system, SPIO@SiO 2 -ANB, which integrates superparamagnetic iron oxide nanoparticles (SPIOs), a silica (SiO 2 ) shell, and the surface-loaded multi-target tyrosine kinase inhibitor anlotinib (ANB). This platform enhances drug stability, enables tumor-targeted delivery, and induces ferroptosis. The synthesized nanoparticles demonstrated a monodisperse spherical morphology, pH-responsive ANB release, and efficient cellular internalization. In vitro, SPIO@SiO 2 -ANB exhibited superior cytotoxicity against A549 and H460 NSCLC cells compared to free ANB, concurrently elevating intracellular reactive oxygen species (ROS) and modulating key ferroptosis-related proteins (COX-2, xCT, GPX4). In vivo studies using xenograft models revealed improved tumor accumulation and retention of SPIO@SiO 2 -ANB, leading to significant tumor growth inhibition, enhanced apoptosis, and suppressed angiogenesis. This work presents a synergistic therapeutic strategy that combines ferroptosis induction with targeted therapy, offering a promising avenue for the safe and effective treatment of NSCLC.
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高影响因子
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