ACS Omega
·
2024
·
IF 3.7
Tengjiao Fan,Lin Shen,Yaxin Huang,Xin Wang,Lijiao Zhao,Rugang Zhong,Peng Wang,Guohui Sun
Lung cancer ranks as the second most diagnosed cancer and the leading cause of cancer-related deaths worldwide. Novel chemotherapeutic strategies are crucial to efficiently target tumor cells while minimizing toxicity to normal cells. In this study, we proposed a combination strategy using energy blocker lonidamine (LND) and cytotoxic drug nimustine (ACNU, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea) to enhance the killing of a human lung cancer cell line and investigated the potential chemo-sensitizing mechanism of LND. LND was found to remarkably increase the cytotoxicity of ACNU to A549 and H1299 cells without significantly affecting normal lung BEAS2B cells. The combination of LND and ACNU also produced significant effects on cell apoptosis, colony formation, cell migration, and invasion assays compared to single drug treatment. Mechanistically, LND decreased intracellular ATP levels by inhibiting glycolysis and inducing mitochondrial dysfunction. Furthermore, the combination of LND and ACNU could intensify cellular oxidative stress, decrease cellular GSH contents, and increase reactive oxygen species (ROS) production. Notably, LND alone dramatically downregulated the expression of DNA repair protein MGMT (O6-methylguanine-DNA methyltransferase), enhancing DNA interstrand cross-link formation induced by ACNU. Overall, LND represents a potential chemo-sensitizer to enhance ACNU therapy through energy inhibition, disrupting redox homeostasis and downregulating MGMT expression in human lung cancer cell line under preclinical and clinical background.
研究领域:
肿瘤学
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药理学
·
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
Cell Death & Disease
·
2026
·
IF 12.2
Sun Zhiming,Deng Yunfang,Liu Yue,Zeng Liyuan,He Chujing,Liu Ye,Liu Zhaohui,Li Jiabing,Sheng Ying,Cai Yuqiao,Xue Yuyao,Zhao Yu
Temozolomide (TMZ) resistance in glioblastoma (GBM) is often linked to high MGMT protein levels, but MGMT-deficient tumors can still acquire resistance, implicating MGMT-independent repair pathways. Here, we identify an oxidative stress-responsive LMO7–ALKBH2 ubiquitination mechanism that regulates ALKBH2 stability and modulates alkylation damage tolerance in GBM. The E3 ligase LMO7 directly binds ALKBH2 and promotes K48-linked polyubiquitination and proteasomal degradation of ALKBH2, with Lys7 serving as a major ubiquitin acceptor site. Oxidative stress enhances LMO7-dependent ALKBH2 ubiquitination through NEDD8-dependent cullin neddylation, reducing TMZ-induced ALKBH2 accumulation and increasing TMZ sensitivity. The K7R substitution attenuates LMO7- and oxidative stress-induced ALKBH2 polyubiquitination and degradation and weakens LMO7-dependent TMZ sensitization. Functionally, ALKBH2 depletion sensitizes MGMT-deficient GBM cells to TMZ and methyl methanesulfonate, whereas ALKBH2 re-expression restores alkylator tolerance. In patient datasets, ALKBH2 protein levels are elevated in GBM and inversely associated with MGMT protein levels, an association not detected at the mRNA level. High ALKBH2 expression in chemotherapy-treated IDH-wild-type glioma and low LMO7 expression in the CGGA astrocytoma cohort are each associated with shorter overall survival. Together, these results indicate that oxidative stress-coupled LMO7-dependent polyubiquitination of ALKBH2 modulates TMZ sensitivity in GBM, particularly in MGMT-deficient tumors.
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2026
·
IF 7.3
Dou Lu,Lijun Zhu,Jing Pan,Jianrui Li,Qing Xu,Liying Wang,Qing-Qing Zhou,Hao Pan,Qiang Wang,Dong Han,Zhiqiang Zhang,Jingxing Guo,Xiaoqing Cheng,Yiqing Wang,Huiming Cai,Xiaoyuan Chen,Longjiang Zhang,Guangming Lu
Glioblastoma (GBM) response to Temozolomide (TMZ) critically depends on O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Clinically, the unmethylated MGMT subtype─representing the predominant GBM population─universally develops TMZ resistance, driving an urgent need for novel therapeutics. While metabolic reprogramming represents a potential therapeutic target, current methylation detection methods cannot provide targetable metabolic information. To elucidate methylation-associated metabolic signatures while mitigating complex biological background noise, we established a stepwise validation framework using CRISPR-engineered cell models. Raman spectroscopy (RS) analyzed CRISPR-dCas9-edited GBM cell lines to extract pure metabolic fingerprints. In MGMT hypermethylated (MGMT-HYPER) GBMs, the saturated fatty acid (SFA) Raman peak was elevated. Conversely, MGMT hypomethylated (MGMT-HYPO) GBMs exhibited enhanced peaks for deoxyribonucleic acid (DNA), amino acids, and unsaturated fatty acids (UFAs). RS-identified metabolites were validated by liquid chromatography–mass spectrometry. Subsequently, uniform manifold approximation and projection (UMAP) effectively clustered HYPER/HYPO Raman spectra. A Raman classification model utilizing a core 13-feature signature from in vitro findings achieved a 94.5% area under the curve (AUC) in distinguishing methylation status across 62 clinical specimens. Correlation analysis demonstrated: (1) a positive correlation of SFA content (1444 cm–1) with methylation levels in MGMT-HYPER tumors; (2) an inverse association of DNA levels (1093 cm–1) with methylation in intermediate-methylation GBMs; and (3) a negative correlation between UFA content (1266 cm–1) and methylation in unmethylated GBMs. This study confirms RS potential for assessing MGMT methylation status in tumors and elucidates metabolic signatures associated with differential methylation in GBMs, providing targets for metabolic intervention against TMZ resistance.
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DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 23
·6791-6803
·
IF 7.59
Yandong Xie,Xueying Lu,Zhen Wang,Mingxi Liu,Liang Liu,Ran Wang,Kun Yang,Hong Xiao,Jianyong Li,Xianglong Tang,Hongyi Liu
Glioblastoma (GBM), as the most aggressive adult brain tumor, seriously threatened people's lives with a low survival time. Standard postoperative treatment, chemotherapy combined with radiotherapy (RT), was the major therapeutic strategy for GBM. However, this therapeutic efficacy was hindered by chemoradiotherapy resistance of GBM. Herein, to sensitize temozolomide (TMZ)-based chemotherapy and RT, a hypoxia-radiosensitive nanoparticle for co-delivering TMZ and siMGMT (RDPP(Met)/TMZ/siMGMT) was synthesized in this study. Our nanoparticle could effectively release the encapsulated alkylating agent (TMZ) and small interfering O6-methylguanine-DNA-methyltransferase RNA (siMGMT) in the hypoxic GBM. DNA-damage repair was effectively inhibited by down-regulating MGMT expression and activating cell apoptosis, which obviously enhanced the sensitivity of TMZ as well as RT. In vitro and in vivo experiments showed that RDPP(Met)/TMZ/siMGMT could efficiently penetrate the blood–brain barrier (BBB), accurately target GBM cells and effectively inhibit GBM proliferation. Compared with traditional TMZ combined with RT, RDPP(Met)/TMZ/siMGMT remarkably improved the survival time of orthotopic GBM-bearing mice, which demonstrated that our nanoplatform was an efficient combinatorial GBM therapy.
研究领域:
肿瘤学
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纳米技术
·
药理学
·
神经科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yu He,Qi-Wen Chen,Jin-Xin Yu,Si-Yong Qin,Wen-Long Liu,Yi-Han Ma,Xiao-Sui Chen,Ai-Qing Zhang,Xian-Zheng Zhang,Yin-Jia Cheng
Temozolomide (TMZ) is an oral DNA-alkylating drug used in colorectal cancer (CRC) chemotherapy. In this work, we proposed a safe and biomimetic platform for macrophages-targeted delivery of TMZ and O 6 -benzylguanine (O 6 -BG). TMZ was loaded in poly (D, l -lactide-coglycolide) (PLGA) nanoparticles , followed by sequential coating with O 6 -BG-grafted chitosan (BG-CS) layers and yeast shell walls (YSW) via layer-by-layer assembly (LBL) process, forming TMZ@P-BG/YSW biohybrids. Due to the yeast cell membrane-camouflage, TMZ@P-BG/YSW particles exhibited significantly enhanced colloidal stability as well as low premature drug leakage in simulated gastrointestinal conditions. In vitro drug release profiles of TMZ@P-BG/YSW particles revealed noticeable higher TMZ release in simulated tumor acidic environment within 72 h. Meanwhile, O 6 -BG could down-regulate MGMT expression in CT26 colon carcinoma cells, ultimately facilitating TMZ-induced tumor cell death. After oral delivery of yeast cell membrane-camouflaged particles containing fluorescent tracer (Cy5), TMZ@P-BG/YSW and bare YSW displayed high retention time of 12 h in the colon and small intestine (ileum). Correspondingly, oral gavage administration of TMZ@P-BG/YSW particles afforded favorable tumor-specific retention and superior tumor growth inhibition. Overall, TMZ@P-BG/YSW is validated to be a safe, targetable and effective formulation, paving a new avenue towards highly effective and precise treatment of malignancies.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Li Yatian,Gao Zhenyue,Wang Yuhong,Pang Bo,Zhang Binbin,Hu Ruxin,Wang Yuqing,Liu Chao,Zhang Xuebin,Yang Jingxuan,Mei Mei,Wang Yongzhi,Zhou Xuan,Li Min,Ren Yu
Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
·
神经肿瘤学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Zekun Li,Mochen Guo,Mingxiao Gu,Zhongtian Cai,Qiuyu Wu,Jia Yu,Meilun Tang,Chenxi He,Yuxuan Wang,Piaoyang Sun,Qidong You,Lei Wang
The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC50 = 33.8/0.9 μM) and improved drug-like properties (favorable stability and safety, F = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor LB-100. Importantly, we found the spatial conformational restriction of the 28a indole fragment was responsible for the selectivity of PP5. Thus, 28a activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.
研究领域:
药理学
·
肿瘤学
·
药物化学
·
癌症生物学
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产品关联
DOI
PubMed
高影响因子
BIOELECTROCHEMISTRY
·
2022
·
IF 5.76
Hongmei Yang,Jing Ren,Mei Zhao,Chen Chen,Fang Wang,Zilin Chen
The detection of methylation level in O 6 -methylguanine-DNA methyltransferase (MGMT) gene is of great significance for diagnosis, prognosis and treatment of glioblastoma. Herein, we proposed an electrochemical immunosensor for detection of MGMT gene methylation. Graphene oxide-magnetic nanoparticles-β-cyclodextrin (GO-Fe 3 O 4 -β-CD) nanocomposite was covered on electrode, and then anti-5-methylcytosine (5mC) antibody was immobilized on modified electrode via host–guest interaction with β-CD. The immobilized antibody specifically recognized and directly captured 5mC on DNA containing MGMT promoter sequence (MGMT-DNA). The methylation level in MGMT-DNA could be evaluated using Ru(NH 3 ) 6 3+ as an electrochemical signal indicator. The redox recycling of Ru(NH 3 ) 6 3+ was triggered by Fe(CN) 6 3− and further amplified current response. A detection limit as low as 0.0825 pM was obtained. Finally, this electrochemical method was successfully applied to analysis of methylated MGMT-DNA in biological sample and detection of other methylation modifications, such as N6-methyladenosine in RNA.
研究领域:
生物医学工程
·
分析化学
·
癌症研究
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Shuai Wu,Ya Wang,Yunfan Li,Minyao Qiu,Yuan Zhong,Maolan Zhang,Haifeng Yang,Jianshu Li,Wei Wu
Clinical treatment of temozolomide (TMZ)-resistant glioblastoma (GBM) remains a significant challenge. This study aims to develop a multifunctional biomimetic Nano-AUTAC (BM@pPPD/TMZ) that can selectively degrade β-catenin via autophagy, thereby overcoming TMZ resistance in GBM. BM@pPPD/TMZ is capable of penetrating the blood-brain barrier (BBB), targeting GBM lesions via microglia-derived membrane camouflage, and inducing degradation of β-catenin through the autophagy-lysosomal pathway. For improving the selective and efficient degradation of β-catenin, BM@pPPD/TMZ is functionalized with a tri-functional peptide comprising a β-catenin-binding domain, a cathepsin B (CTSB)-cleavable GLFG linker, and a phosphatidylserine (PS)-targeting motif. In the GBM microenvironment, the elevated CTSB triggers linker cleavage, promoting membrane shedding and enhancing the cellular uptake. Meanwhile, the incorporation of the cationic lipid DOTAP promotes autophagosome formation, further facilitating degradation of β-catenin. Both in vitro and in vivo studies demonstrate that BM@pPPD/TMZ is able to effectively penetrate the BBB and accumulate within tumor lesion, concurrently promoting β-catenin degradation and MGMT downregulation. This finding provides a promising nanotherapeutic strategy for overcoming TMZ resistance and improving GBM therapeutic efficacy.
研究领域:
纳米医学
·
癌症治疗
·
分子生物学
·
神经肿瘤学
·
自噬研究
·
药物递送
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）