EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
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IF 6.7
Hongyan Lin,Hongwei Han,Minkai Yang,Zhongling Wen,Qingqing Chen,Yudi Ma,Xuan Wang,Changyi Wang,Tongming Yin,Xiaoming Wang,Guihua Lu,Hongyuan Chen,Jinliang Qi,Yonghua Yang
Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis , but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity , we proposed a “two-step approach” that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin ( SK ) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC 50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC 50 = 4.56 μmol/L) and the positive control gefitinib (IC 50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK . Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes , thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5 , a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation.
研究领域:
肿瘤学
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药理学
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癌症生物学
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代谢途径
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
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2020
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IF 2.365
Zhongjuan Wang,Yueqin Liang,Yanqiu Liu,Hongying Xia,Jianqi Liu,Xingfang Jin,Zhongkun Li
Multi-drug resistance (MDR) is one of the major challenges in the successful chemotherapy of non-small cell lung cancer (NSCLC). Although RNA interference (RNAi) has been widely used to silence resistance-related genes, the effect remains unsatisfactory. In this study, we attempted to overcome MDR of NSCLC by simultaneously interfering with two RNAs that have different functions. A new pH-triggered polyglutamate brush polymer dimethylmaleic anhydride-poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (DMA-mPEG-b-PG-g-spermine, DPPGS) was designed and synthesized. The DPPGS/small interfering RNA (siRNA) complex nanoparticles (DPPGSN) were prepared. The results demonstrated that DPPGSN could be transformed from a negatively charged form into a positively charged form in the slightly acidic tumor extracellular environment. The siRNA targeting MDR1 mRNA (siMDR1) and siRNA targeting survivin mRNA (siSurvivin) could be efficiently co-delivered by DPPGS to simultaneously interfere with two genes (p < 0.01). Furthermore, DPPGS co-delivery of siMDR1 and siSurvivin lowered the IC50 value of cisplatin (DDP) in A549/DDP (p < 0.01) cells and increased the apoptosis rate of the cells (p < 0.01). Therefore, co-delivery of siMDR1 and siSurvivin using DPPGS would be a promising approach for overcoming MDR of NSCLC.
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
Communications Biology
·
2024
·Vol. 7
·期 1
·1-15
·
IF 5.2
Zhang Wen,Cai Shuhui,Qin Lihong,Feng Yaru,Ding Menglei,Luo Zichen,Shan Jinjun,Di Liuqing
Aconiti Lateralis Radix Praeparata ( Fuzi in Chinese) is widely used in the clinical treatment of tumors. This study aims to explore the active fractions and underlying mechanisms of Fuzi in the treatment of non-small cell lung cancer (NSCLC). Fuzi alkaloids (FZA) is prepared and found to inhibit the growth of NSCLC both in vitro and in vivo significantly. A total of 53 alkaloids are identified in FZA by UPLC-Q-TOF-MS. Proteomics experiment show that 238 differentially expressed proteins regulated by FZA are involved in amino acid anabolism, pyrimidine metabolism and PI3K/Akt-mTOR signaling pathway. Metabolomics analyses identify 32 significant differential metabolites which are mainly involved in amino acid metabolism, TCA cycle and other pathways. Multi-omics research combined with molecular biological assays suggest that FZA might regulate glycolysis through PI3K/Akt-mTOR pathway to treat NSCLC. The study lays a foundation for the anti-cancer investigation of Fuzi and provides a possible scientific basis for its clinical application.
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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生物化学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2024
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IF 4.3
Xin Zhao,Chao Chen,Weina Han,Min Liang,Yuanyuan Cheng,Yingjie Chen,Defeng Pang,Haoqi Lei,Xuefei Feng,Shifeng Cao,Zhixiong Li,Jinhui Wang,Yan Zhang,Baofeng Yang
Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.
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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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2024
·
IF 2.8
Yang Chen,Shujun Bao,Zhongzhao Wang,Zheng Fang,Hao Tang
Background Cisplatin (DDP) chemotherapy is commonly used in therapy for non-small cell lung cancer (NSCLC), but increased drug resistance has become a huge obstacle. Baicalin (BA) contributed to the sensitivity of NSCLC to DDP. Here, we aimed to further probe the pathophysiological mechanisms of BA in NSCLC. Methods A549 and A549/DDP cells and xenograft mice were treated with BA and DDP. Xenograft mice were treated additionally with the NRF2 inducer (Bardoxolone methyl, BM) and KEAP1 knockdown. The levels of ferritinophagy-related proteins and biomarkers were determined. The autophagosomes were observed. M1 macrophage polarization and the contents of related indicators were analyzed. The involvement of KEAP1/NRF2/HO-1 was determined. Results BA inhibited cell development, and the effect of BA and DDP on cell development was additive. The abundance of ferritinophagy-related proteins and the number of autophagosomes were induced by BA. BA also promoted the transition of GSH to GSSH. BA favored M1 macrophage polarization and affected the expression of related proteins. When BA and DDP combined, these molecular phenomena were further exacerbated. BA induced accumulation of KEAP1 and reduction of NRF2 and HO-1. However, BM and KEAP1 knockdown disrupted the synergistic effects of BA and DDP on inhibiting NSCLC growth. BM and KEAP1 knockdown reversed DDP and BA-promoted protein expression activity and M1 macrophage polarization. Conclusion Our findings suggest that BA is involved in ferritinophagy and macrophage immunity through the KEAP1-NRF2/HO-1 axis, thereby improving the DDP sensitivity in NSCLC, which could provide new candidates for treatment strategies.
研究领域:
肿瘤学
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药理学
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免疫学
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分子生物学
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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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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2025
·
IF 3.4
Yun Chen,Yang Wang,Shuai Shen,Libin Zhang,Jun Liu,Xiangyun Yan,Hao Peng,Zheyuan Xu
RHDBB1 could arrest cell cycle in the TP53 mutant NCI-H596 cells; RHDBB1 promotes NSCLS by reducing DNA-PKcs dependent cells apoptosis; Targeting both TP53 and RHDBB1 may have beneficial effects on NSCLC.
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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癌症研究
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DOI
PubMed
高影响因子
CANCER LETTERS
·
2018
·
IF 6.491
Yingming Sun,Hongtao Miao,Shijing Ma,Lei Zhang,Chengcheng You,Fang Tang,Cui Yang,Xiaoli Tian,Feng Wang,Yuan Luo,Xiangjie Lin,Hui Wang,Chunyang Li,Zhijun Li,Hongnv Yu,Xuefeng Liu,Yu Xiao,Yan Gong,Junhong Zhang,Hong Quan,Conghua Xie
FePt-Cys nanoparticles (FePt-Cys NPs) have been well used in many fields, despite their poor solubility and stability. We synthetized a cysteine surface modified FePt NPs, which exhibited good solubility, stability and biocompatibility. We explored the insight mechanisms of the antitumor effects of this new nanoparticle system in lung cancer cells. In the in vitro study, FePt-Cys NPs induced a reactive oxygen species (ROS) burst, which suppressed the antioxidant protein expression and induced cell apoptosis. Furthermore, FePt-Cys NPs prevented the migration and invasion of H1975 and A549 cells. These changes were correlated with a dramatic decrease in MMP-2/9 expression and enhanced the cellular attachment. We demonstrated that FePt-Cys NPs promoted the effects of chemo-radiation through activation of the caspase system and impairment of DNA damage repair. In the in vivo study, no severe allergies or drug-related deaths were observed and FePt-Cys NPs showed a synergistic effect with cisplatin and radiation. In conclusion, with good safety and efficacy, FePt-Cys NPs could therefore be potential sensitizers for chemoradiotherapy.
研究领域:
纳米医学
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肿瘤学
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药理学
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放射生物学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Shuaijun Li,Caiting Meng,Qian Hao,Ruina Zhou,Luyao Dai,Yucheng Guo,Sitong Zhao,Xin Zhou,Chunju Lou,Ji Xu,Peng Xu,Jinfan Yang,Yifan Ding,Yanni Lv,Shengli Han,Shuai Li,Jing Li,Huafeng Kang,Zhengtao Xiao,Mingqian Tan,Xiaobin Ma,Hao Wu
Non-small cell lung cancer (NSCLC) brain metastases present a significant treatment challenge due to limited drug delivery efficiency and severe adverse reactions . In this study, we address these challenges by designing a “on/off” switchable crosslinked paclitaxel (PTX) nanocarrier , BPM-PD, with novel ultra-pH-sensitive linkages (pH 6.8 to 6.5). BPM-PD demonstrates a distinct “on/off” switchable release of the anti-cancer drug paclitaxel (PTX) in response to the acidic extratumoral microenvironment. The “off” state of BPM-PD@PTX effectively prevents premature drug release in the blood circulation, blood-brain barrier (BBB)/blood-tumor barrier (BTB), and normal brain tissue, surpassing the clinical PTX-nanoformulation (nab-PTX). Meanwhile, the “on” state facilitates precise delivery to NSCLC brain metastases cells. Compared to nab-PTX, BPM-PD@PTX demonstrates improved therapeutic efficacy with a reduced tumor area (only 14.6%) and extended survival duration, while mitigating adverse reactions (over 83.7%) in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), offering a promising approach for the treatment of NSCLC brain metastases. The precise molecular switch also helped to increase the PTX maximum tolerated dose from 25 mg/kg to 45 mg/kg This research contributes to the field of cancer therapeutics and has significant implications for improving the clinical outcomes of NSCLC patients.
研究领域:
肿瘤学
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药学
·
纳米技术
·
癌症治疗
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产品关联
DOI
PubMed
高影响因子
MEDICAL ONCOLOGY
·
2016
·Vol. 33
·期 2
·1-9
·
IF 2.486
Li Yang-ling,Pan Yi-ni,Wu Wen-jue,Mao Shi-ying,Sun Jiao,Zhao Yi-ming,Dong Jing-yin,Zhang Da-yong,Pan Jian-ping,Zhang Chong,Lin Neng-ming
Erlotinib is effective in NSCLC patients with known drug-sensitizing EGFR mutations, but its clinical efficacy in patients with wild-type EGFR or acquired resistance to erlotinib remains modest. Evodiamine is a chemical extracted from the Evodia rutaecarpa (Juss.) Benth, we showed that evodiamine could induce anti-proliferation and apoptosis in four wild-type EGFR NSCLC cell lines, and combining evodiamine with erlotinib might successfully inhibit cell proliferation and survival in wild-type EGFR NSCLC cells, characterized as erlotinib-resistant. In addition, evodiamine plus erlotinib significantly increased the apoptotic rate of NSCLC cells, as compared to single agent treatment alone. Further investigation of the mechanism underlying these effects revealed that evodiamine plus erlotinib might downregulate Mcl-1 expression through the mTOR/S6K1 control of its translation. Thus, our study has revealed evodiamine as a pertinent sensitizer to erlotinib and the strategy of combining erlotinib with evodiamine appears to be an attractive option for reversing resistance to erlotinib.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2019
·
IF 5.808
Yan Chen,Chen Chen,Xiaojuan Zhang,Chuanchuan He,Pengxuan Zhao,Minsi Li,Ting Fan,Ruicong Yan,Yao Lu,Robert J. Lee,Muhammad Waseem Khan,Muhammad Sarfraz,Xiang Ma,Tan Yang,Guangya Xiang
Platinum-based chemotherapy is used for non-small cell lung cancer (NSCLC). However, it has side effects and minimum efficacy against lung cancer metastasis. In this study, platinum–curcumin complexes were loaded into pH and redox dual-responsive nanoparticles (denoted as Pt– [email protected] ) to facilitate intracellular release and synergistic anti-cancer effects. Pt– [email protected] was prepared by a nano-precipitation method and had a diameter of ∼100 nm. The nanoparticles showed increased anti-cancer effects both in vivo and in vitro . In addition, Pt– [email protected] blocked PI3K/AKT signal transduction pathway and inhibited MMP2 and VEGFR2, resulting in enhanced anti-metastatic activity. Furthermore, reduced side effects were also observed. In conclusion, Pt– [email protected] provided a novel and attractive therapeutic strategy for NSCLC.
研究领域:
药理学
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肿瘤学
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纳米技术
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化疗
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Mengxuan Zhang,Xuxiang Zheng,Lanyue Kou,Lizhu Xiao,Huan Cai,Tao Hu,Yujiao Ma,Anyi Chen,Min Zhao
In situ -engineered NU-1000@Gra gives 2.20-fold ECL enhancement via dual paths, surmounting single-component trade-off. • First Zr-MOF/graphene synergistically boosts ECL, lifting quantum yield from 11.89% to 15.69% via excited-state optimization. • TDN strategy enhances stability and anti-interference, enabling PD-L1 + tEV detection with LOD 899.35 particles/mL. • NGTA platform detects NSCLC with 100% sensitivity, 90.91% accuracy, 32.09-fold lower LOD than ELISA for tEV biopsy. Tumor-derived PD-L1 + extracellular vesicles (PD-L1 + tEVs) represent valuable liquid-biopsy biomarkers for non-small-cell lung cancer, whereas their reliable quantification is largely restricted by low abundance and complex matrix interference. Herein, we fabricated an in-situ engineered NU-1000@Graphene (Gra) nanohybrid as a kinetics-efficiency dual-boosted electrochemiluminescence (ECL) emitter to build the N U-1000@ G ra t etrahedral a ptasensor (NGTA). Benefiting from intimate interfacial coupling, Gra acted as a bifunctional accelerator in the NU-1000/S 2 O 8 2− system, accelerating interfacial electron transfer and sulfate radical production to realize a 1.58-fold improvement in ECL kinetics and a 1.39-fold enhancement in luminescence efficiency. Assisted by the tetrahedral DNA nanostructure scaffold that suppressed non-specific adsorption, the NGTA achieved an ultralow detection limit of 899.35 particles/mL for PD-L1 + tEVs. Preliminary clinical results demonstrated its diagnostic potential. This work underscores the significance of metal-organic framework (MOF)-Gra interfacial engineering for synergistic ECL amplification, providing a rational material design paradigm for high-performance liquid-biopsy biosensors.
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高影响因子
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