Nature Nanotechnology
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2021
·Vol. 16
·期 10
·1150-1160
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IF 39.213
Shao Ximing,Ding Zhihao,Zhou Wenhua,Li Yanyan,Li Zhibin,Cui Haodong,Lin Xian,Cao Guoli,Cheng Binghua,Sun Haiyan,Li Meiqing,Liu Ke,Lu Danyi,Geng Shengyong,Shi Wenli,Zhang Guofang,Song Qingle,Chen Liang,Wang Guocheng,Su Wu,Cai Lintao,Fang Lijing,Leong David Tai,Li Yang,Yu Xue-Feng,Li Hongchang
Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle’s centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.
研究领域:
纳米技术
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癌症生物学
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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
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2025
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IF 5.4
Hong Zhou,Lixia Guan,Guoqiang Lin,Xiaotian Yang,Xingxia Zhang,Yejun Si,Yanming Zhang,Juan Chen
Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1–5) targeting the polo box domain (PBD) of PLK1 through an integrated virtual screening strategy. MST assays confirmed that PLs 1–5 had strong binding affinity for PLK1, especially PL-1 (Kd = 3.11 ± 0.05 nM). Meanwhile, the kinase selectivity assay showed that the PL-1 had no significant inhibitory effects on a panel of other kinases. Molecular dynamics simulation further demonstrated the structural stability of PL-1 and PLK1 complex. Notably, PL-1 displayed potent antiproliferative efficacy against U266 multiple myeloma cells (IC50 = 0.09 ± 0.01 µM). PL-1 showed high intracellular uptake capacity. In addition, PL-1 exhibited good biostability in human serum and liver microsomes. Taken together, PL-1 is a potent and highly selective antitumor agent with considerable therapeutic promise for multiple myeloma.
研究领域:
肿瘤学
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分子生物学
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药物化学
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转化医学
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生物信息学
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药理学
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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
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IF 6.3
Qian Hu,Mengyao Wang,Meng Chen,Jinjin Wang,Ting Niu
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma, with two-thirds of patients relapsing or resisting existing therapies, highlighting the urgent need for effective treatments. Toosendanin (TSN), a triterpenoid from Meliae Cortex, exhibits significant anti-cancer activity by modulating cell survival and proliferation. This study investigates the anti-lymphoma effects and underlying mechanisms of TSN, proposing it as a potential therapeutic agent to address the challenges of DLBCL. Network pharmacology, molecular docking, and transcriptome sequencing were employed to predict TSN's anti-DLBCL potential. Findings were validated through in vitro and in vivo experiments, including cell viability assays, flow cytometry, quantitative PCR, Western blotting, reverse experiments with small-molecule inhibitors or genetic editing, and a cell-derived xenograft (CDX) model. Bioinformatics analyses revealed TSN's strong binding affinity to PI3Kα/β and Polo-like kinase 1 (PLK1). Experiments showed that TSN downregulated the PI3K/Akt signaling pathway and reduced PLK1 mRNA and protein levels, inducing apoptosis, cell cycle arrest, and cell death in DLBCL cells. RNA sequencing and metabolic assays indicated TSN upregulated cholesterol biosynthesis in DLBCL cells. Co-treatment with a statin enhanced TSN's anti-DLBCL effects while mitigating hepatic and pulmonary toxicity. This study identifies TSN as a dual inhibitor of PI3K and PLK1 with significant therapeutic potential for DLBCL. It also proposes a lipid-modulating strategy to enhance TSN's cytotoxicity while reducing adverse effects, offering a promising approach to improve DLBCL treatment outcomes.
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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生物信息学
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DOI
PubMed
高影响因子
MOLECULES
·
2019
·Vol. 24
·期 18
·3413
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IF 3.06
Ehexige Ehexige,Tsogzolmaa Ganbold,Xiang Yu,Shuqin Han,Huricha Baigude
Lipid nanoparticles (LNP) are the most potent carriers for the delivery of nucleic acid-based therapeutics. The first FDA approved a short interfering RNA (siRNA) drug that uses a cationic LNP system for the delivery of siRNA against human transthyretin (hTTR). However, preparation of such LNP involves tedious multi-step synthesis with relatively low yields. In the present study, we synthesized cationic peptidomimetic functionalized cholesterol (denote Chorn) in straightforward chemical approaches with high yield. When formulated with helper lipids, Chorn LNPs complexed with siRNA to form nanoparticles with an average diameter of 150 nm to 200 nm. Chorn LNP mediated transfection of a green fluorescence protein (GFP) expressing plasmid resulted in 60% GFP positive cells. Moreover, Chorn LNP delivered siRNA against polo-like kinase 1 (Plk1), a disease related gene in cancer cells and efficiently suppressed the expression of the gene, resulting in significant morphological changes in the cell nuclei. Our data suggested that cholesterol based cationic LNP, prepared through a robust chemical strategy, may provide a promising siRNA delivery system.Keywords:siRNA;lipid nanoparticle;peptidomimetic;cholesterol;Plk1
研究领域:
药学
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纳米技术
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NEURO-ONCOLOGY
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2026
·Vol. 178
·期 2
·50
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IF 3.4
Zhang Yinghao,Wang Haoran,Wang Jinhai,Sui Yufang,Zhang Wanhong,Lin Xuhong,Zhang Pengpai
Background SNAREs participate in tumor progression; however, existing studies on SNAREs remain fragmented. The discovery of suitable SNARE targets and delineation of their application limits are critical. Methods We performed integrative analyses on clinical data and RNA-seq data from TCGA to identify therapeutic targets in defined cancer subtypes. These in silico findings were substantiated in patient-derived tumor sections, glioma cell lines, and xenografts. Gene/microRNA expression was modulated through lentiviral transduction. Omics methods, including RNA-seq, microRNA sequencing, and data-independent acquisition proteomics, were used to localize/quantify downstream effectors, followed by characterization with antibody-based tests. MicroRNA sponge constructs were validated with qPCR. Results We evaluated VAMP5 as a glioma-selective therapeutic target and found two distinct response phenotypes following VAMP5 knockdown (KD). In the VAMP5‐KD-sensitive subgroup, VAMP5 depletion universally suppressed PLK1, partly by reducing novel upregulatory microRNAs (miR-1301-3p and miR-12135), thereby inhibiting tumor cell proliferation. However, PLK1 expression remained unchanged in VAMP5‐KD-insensitive tumors, making PLK1 a reliable pharmacodynamic marker. High NDRG4 expression predicted sensitivity to VAMP5 KD. NDRG4 overexpression induced in insensitive glioma lines converted them to a sensitive phenotype, enabling VAMP5-KD-induced PLK1 downregulation through coordinated modulation of additional microRNAs (classical tumor-suppressive miR-509-5p upregulation and novel upregulatory miR-1185-3p downregulation) and TNKS reduction (which was also shown to contribute to PLK1 downregulation in a subset of VAMP5-KD-sensitive lines). This NDRG4 OE plus VAMP5 KD cascade also diminished the immune checkpoint ligand VCAM1. We identified LGALS1 as a universal VAMP5‐coexpressed immune modulator, suggesting that VAMP5 KD may further enhance antitumor immunity by downregulating LGALS1. Conclusions Our work provides a preliminary mechanistic framework for VAMP5 KD-mediated glioma suppression on proliferation or immune evasion and highlights several translational opportunities.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2018
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IF 3.909
Tsogzolmaa Ganbold,Shuqin Han,Agula Hasi,Huricha Baigude
Natural carbohydrate polymer-based nanoparticles have great biocompatibility that is required for the safe delivery of various drugs including nucleic acid therapeutics. Herein, we designed curdlan-based nanoparticles for cancer cell targeted delivery of short interfering RNA (siRNA). iRGD peptide conjugated 6-amino-6-deoxy curdlan specifically delivered siRNA to integrin expressing cancer cells. Incubation of cancer cells with free iRGD peptide competitively blocked cellular uptake of the iRGD functionalized curdlan nanoparticles. Chloroquine but not nystatin inhibited cellular uptake of iRGD functionalized curdlan nanoparticles, indicating that the iRGD peptide conjugated curdlan nanoparticles were internalized through the receptor (clathrin)-mediated endocytosis. Moreover, a disease related gene Plk1 was substantially knocked down by siRNA carried by 6AC-iRGD nanoparticles in HepG2 cells. Our data suggested that iRGD functionalized curdlan may provide a biocompatible carrier for siRNA delivery.
研究领域:
生物医学工程
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分子生物学
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药剂学
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DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
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2025
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IF 3.6
Xing Zhou,Zhaokai Zhou,Xiaohan Qin,Jian Cheng,Yongcheng Fu,Yuanyuan Wang,Jingyue Wang,Pan Qin,Da Zhang
Neuroblastoma (NB) remains associated with high mortality and low initial response rate, especially for high-risk patients, thus warranting exploration of molecular markers for precision risk classifiers. Through integrating multiomics profiling, we identified a range of hub genes involved in cell cycle and associated with dismal prognosis and malignant cells. Single-cell transcriptome sequencing revealed that a subset of malignant cells, subcluster 1, characterized by high proliferation and dedifferentiation, was strongly correlated with the hub gene signature and orchestrated an immunosuppressive tumor microenvironment (TME). Furthermore, we constructed a robust malignant subcluster 1 related signature (MSRS), which was an independent prognostic factor and superior to other clinical characteristics and published signatures. Besides, TME differences conferred remarkably distinct therapeutic responses between high and low MSRS groups. Notably, polo-like kinase-1 (PLK1) was one of the most crucial contributors to MSRS and remarkably correlated with malignant subcluster 1, and PLK1 inhibition was effective for NB treatment as demonstrated by in silico analysis and in vitro experiments. Overall, our study constructs a novel molecular model to further guide the clinical classification and individualized treatment of NB.
研究领域:
肿瘤学
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生物信息学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2022
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IF 11.6
Yue Zhou,Lei Xu,Zhangding Wang,Hongwen Liu,Xiang Zhang,Chuanjun Shu,Meng Zhang,Ting Wang,Xinyun Xu,Xiaohong Pu,Jian He,Pin Wang,Yudong Qiu,Guifang Xu,Xiaoping Zou,Yun Zhu,Lei Wang
Rationale : Synergistic treatment strategies for two or more drugs have gradually developed as the main options in clinics for cholangiocarcinoma (CCA) owing to the complicated crosstalk between the tumor and stroma. However, the different synergetic mechanisms pose great challenges to the dosages and order of administration of drugs. Thus, a strategy for exploring and intervening in mutual targets derived from stromal cells and cholangiocarcinoma cells was proposed. Methods : Genes with overexpression patterns in tumors and displaying a significant association with overall survival were identified from RNA-seq data of human CCA patients and CCA mouse models. Western blotting, qRT-PCR, immunofluorescence (IF), colony formation and flow cytometry assays were conducted to determine the biological roles of the key oncogene in cholangiocarcinoma and stromal cells respectively. Additionally, a dual-targeting drug delivery system (AA-HA-ODA) for cancer-associated fibroblasts (CAFs) and tumor cells was constructed to verify the effectiveness of intervening the screened genes in vivo . Results : Polo-like kinase 1 (PLK1) was verified to play vital role in the malignant proliferation of CCA by regulating the cell cycle pathway. PLK1 also decreased stromal production by regulating the CAF phenotype. In addition, a PLK1 inhibitor (Ro3280) loaded dual-targeting drug delivery system (AA-HA-ODA) was prepared and exhibited high affinity for CAFs and cholangiocarcinoma cells. The in vivo distribution pattern and antitumor efficacy of AA-HA-ODA/Ro also verify the effectiveness of inhibiting PLK1 in CCA in vivo . Conclusion : In summary, PLK1 is a mutual target derived from tumor cells and stroma due to its crucial role in the proliferation of tumor cells and stroma regulation in CAFs, which might provide enlightenment for multitarget treatment strategies and guidance for clinical cholangiocarcinoma treatment.
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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癌症治疗
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2020
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IF 5.115
Lu Hou,Zheyu Song,Zhonghang Xu,Yuanyu Wu,Wei Shi
Background siRNA-mediated polo-like kinase 1 (PLK1) silencing has been proposed as a promising therapeutic method for multiple cancers. However, the clinic application of this method is still hindered by the low specific delivery of siPLK1 to desired tumor lesions. Herein, folate (FA)-modified and leucine-bearing polyethylenimine was successfully synthesized and showed excellent targeted silencing to folate receptor overexpressed cells. Materials and Methods The condensation of siPLK1 by FA-N-Ac-L-Leu-PEI (NPF) was detected by the gel retardation assay. The targeted and silencing efficiency was evaluated by flow cytometry and confocal laser scanning microscope. The PLK1 expressions at gene or protein levels were detected by quantitative real-time PCR and Western blotting assay. Further impacts of the PLK1 silencing on cell viability, cell cycle, migration, and invasion were studied by MTT, colony formation, wound healing and transwell assays. Results The NPF and siPLK1 could efficiently assemble to stable nanoparticles at a weight ratio of 3.0 and showed excellent condensation and protection effect. Owing to the FA-mediated targeted delivery, the uptake and silencing efficiency of NPF/siPLK1 to SGC-7901 cells was higher than that without FA modification. Moreover, NPF-mediated PLK1 silencing showed significant antitumor activity in vitro. The anti-proliferation effect of PLK1 silencing was induced via the mitochondrial-dependent apoptosis pathway with the cell cycle arrest of 45% at G2 phase and the apoptotic ratio of 28.3%. Conclusion FA-N-Ac-L-Leu-PEI (NPF) could generate targeted delivery siPLK1 to FA receptor overexpressed cells and dramatically downregulate the expression of PLK1 expression.
研究领域:
癌症研究
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分子生物学
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药学
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纳米技术
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2018
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IF 4.37
Menghao Shi,Xiufeng Zhao,Jiulong Zhang,Shuang Pan,Chunrong Yang,Ying Wei,Haiyang Hu,Mingxi Qiao,Dawei Chen,Xiuli Zhao
Introduction Specific polo-like kinase (PLK1) silencing with small interface RNA (siRNA) may be an effective approach for PLK1-overexpressed lung cancer. However, low siRNA concentration into cytoplasm of tumor tissue severely limits its application. Materials and methods In this study, a novel triblock copolymer methoxy poly(ethylene glycol)-poly(histidine)-poly(sulfadimethoxine) (mPEG-PHis-PSD, shorten as PHD) was synthesized and used to construct novel nonviral gene vector with cationic liposomes. Results The resulting hybrid nanoparticles (PHD/LR) loaded with siPLK1 possessed excellent physiochemical properties. In vitro study indicated that PHD/LR could be efficiently internalized into human lung adenocarcinoma A549 cells and downregulated PLK1 protein expression to induce cell apoptosis, which was attributed to pH-induced instantaneous dissociation, efficient endo/lysosomal escape arose from PHD copolymer. Furthermore, in vivo antitumor activity demonstrated that PHD/LR could efficiently accumulated into tumor tissue and silenced PLK1 expression to possess antitumor activity. Conclusion Taken all these together, PHD/LR was expected to be a suitable carrier for specific delivering siRNA for lung cancer therapy.
研究领域:
癌症研究
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纳米技术
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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
Heliyon
·
2024
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IF 3.4
Qi Wu,Xue-li Ge,Zi-kai Geng,Hao Wu,Jing-yi Yang,Shi-rong Cao,Ai-lin Yang
HuaChanSu is active water extracts from the skin of Bufo bufo gargarizans Cantor. It has been already used to treat clinical cancers including HCC (Hepatocellular carcinoma, HCC), however, the molecular mechanisms under HuaChanSu's anti-cancer effects remain unclear. PPP (Pentose phosphate pathway, PPP), the major source of ribose and NADPH (Nicotinamide adenine dinucleotide phosphate, NADPH), is always over-activated and particularly critical for tumor cells growth. In this study, firstly, we illustrate that HuaChanSu restrains the growth of human hepatoma cells. More importantly, we demonstrate that the expression of G6PD (Glucose-6-phosphate dehydrogenase, G6PD), the first rate-limiting enzyme of the PPP, is restrained in human hepatoma cells after treatment with HuaChanSu. Additionally, our results show that G6PD enzyme activity and dimer formation are inhibited by HuaChanSu. Furthermore, we find that HuaChanSu could inhibit NADPH production and nucleotide level. In addition, we identify that expression of PLK1 (Polo-like kinase 1, PLK1) is also reduced in response to HuaChanSu, and knockdown of PLK1 restrains enzyme activity and dimer formation of G6PD, but has no effect on G6PD protein level. Subsequently, we demonstrate that inhibition of G6PD could restrain the proliferation of tumor cells and enhance the inhibitory effect of HuaChanSu on cell proliferation of human hepatoma cells. In conclusion, for the first time, our study reveals that HuaChanSu interferes with PPP via suppression of G6PD expression and enzyme activity to restrain growth of tumor cells, and these results provide a novel insight for the anti-hepatoma mechanisms of HuaChanSu and promote the innovation of the research model of TCM. Moreover, the development of drugs targeting abnormal tumor metabolism is currently a hot topic, our works provide theoretical support for further drug development from HuaChanSu, meanwhile, the revelation of the new molecular mechanism also provides a new perspective for the study of the pathogenesis of liver cancer.
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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癌症代谢
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）