Frontiers in Pharmacology
·
2025
·
IF 4.8
Ruibing Wu,Hengye Yuan,Yuehua Wang,Xianggang Gou,Wanhua Hou,Zhongzheng Zhou,Xinran Wang,Xiuling Deng,Changshan Wang,Haisheng Wang,Jia Yan
Background: Norcantharidin (NCTD), a bioactive compound derived from traditional Chinese medicine, has demonstrated promising anticancer activity against multiple malignancies, particularly hepatocellular carcinoma (HCC). However, its epigenetic regulatory mechanisms and associated transcriptional consequences remain poorly characterized.Methods: In this study, we integrated biochemical assays with a panel of cellular analyses assessing cell viability, proliferation, colony formation, and migratory capacity to investigate NCTD’s therapeutic potential in HCC progression. Potential molecular targets of NCTD were systematically identified through integrated network pharmacology approaches. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) was performed to quantify H3K27me3 enrichment level at the TOP2A locus in NCTD-treated HCC cells. Molecular docking simulations were employed to examine structural interactions between NCTD and EZH2 (enhancer of zeste homolog 2), while co-immunoprecipitation assays were further conducted to validate protein-protein interactions between EZH2 and protein phosphatase 1 (PP1).Results: We identified topoisomerase IIα (TOP2A) as a critical molecular target mediating NCTD’s anti-HCC effects. Functional characterization revealed that NCTD significantly attenuated HCC cell proliferation and induced G2/M phase cell cycle arrest through disruption of the TOP2A-p53 signaling axis. Mechanistic investigations demonstrated that NCTD epigenetically suppresses TOP2A transcription via PRC2 (Polycomb Repressive Complex 2)-mediated deposition of the repressive histone mark H3K27me3 at the TOP2A promoter. Structural biology analyses confirmed direct binding of NCTD to EZH2 protein, consequently impairing PP1-mediated dephosphorylation and enhancing PRC2 complex stability.Conclusion: Our findings establish that NCTD exerts anticancer effects in HCC through epigenetic silencing of TOP2A. This work not only elucidates a novel pharmacoepigenetic mechanism underlying NCTD’s antitumor activity but also provides translational rationale for developing PRC2-targeted therapeutic strategies in HCC management.
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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DOI
PubMed
高影响因子
AAPS PHARMSCITECH
·
2023
·Vol. 24
·期 5
·1-9
·
IF 3.3
Kuang Hailong,Wang Peipei,Wang Yuhang,Li Jinbo,Yu Jiang,Jia Lirui,Li Shuo,Ma Yan,Liu Hongzhuo,He Zhonggui,Wang Yongjun
To address the limitations of norcantharidin (NCTD) in clinical applications, including restricted tumor accumulation and intense irritation, we have developed a new derivative of NCTD with (S)-1-benzyl-3-pyrrolidinol, which can be actively loaded into liposomes to achieve drug encapsulation and sustained release properties by using pH gradient loading technique. Cytotoxicity tests against cancer cell lines (Hepa 1–6 and 4 T1 cells) have demonstrated that this derivative exhibits comparable activity to NCTD in vitro . The NCTD derivative can be efficiently loaded into liposomes with high encapsulation efficiency (98.7%) and high drug loading (32.86%). Tolerability and antitumor efficacy studies showed that the liposomal NCTD derivative was well tolerated at intravenous injection doses of 3 folds higher than the parent drug solution, while significantly improved anticancer activity in vivo was achieved. This liposomal nanodrug could become a potent and safe NCTD formulation alternative for cancer therapy. Graphical abstract
研究领域:
药理学
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肿瘤学
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纳米医学
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PubMed
高影响因子
JOURNAL OF MATERIALS CHEMISTRY
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2012
·Vol. 22
·期 31
·15804-15811
·
IF 5.968
Kedong Lu,Mingzhuo Cao,Weiwei Mao,Xuanrong Sun,Jianbin Tang,Youqing Shen,Meihua Sui
Amides with β-carboxylic acid groups are stable and negatively charged at physiological pH, but hydrolyze back to the corresponding amines and anhydrides once in an acidic environment. We thereby developed charge-reversal nanocarriers for drug delivery. In these systems, the anhydrides served only as groups to amidize the amines in cationic polymers and had no therapeutic use after being cleaved from the carrier in the cells. Herein, we utilized the characteristic anhydride structure of norcantharidin (NCTD) and the pH-dependent hydrolysis of its β-carboxylic amides and developed novel acid-labile conjugates for the targeted delivery of NCTD. In this study, NCTD was used as both an anticancer drug and an acid-labile anhydride to react with cationic polymers including PEI and PLL to form β-carboxylic amides. The obtained conjugates (PEI–NCTD and PLL–NCTD) had not only significantly improved NCTD solubility and high drug loading contents (as high as 72.3% and 56.8%, respectively, for PEI–NCTD and PLL–NCTD), but also favorable acid-labile capabilities. These conjugates were stable and negatively charged at neutral pH, but once in acidic environments (e.g. endo/lysosomes), they hydrolyzed and regenerated not only NCTD as an antitumor drug, but also the PEI or PLL, which could assist the endo/lysosomal escape and release of the drugs. Further, functionalizing the acid-labile conjugates with targeting moiety folic acid (FA) increased the cellular uptake of the conjugates into folate receptor-overexpressing tumor cells and thereby the in vitro cytotoxicity. These targeted acid-labile conjugates may help to reduce the side effects of NCTD and improve its clinical applications.
研究领域:
药物化学
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肿瘤学
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药物递送系统
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DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2025
·
IF 2.2
Jingming Luo,Yanni Shan,Xudong Fan,Chongyang Wu,Luting Lin,Zeng Wang,Xinjun Cai
Anti-angiogenic drugs are theorized to suppress tumor growth by blocking neovascularization. Notably, low-dose regimens may transiently normalize tumor vasculature. However, their rapid systemic clearance limits sustained vascular modulation. This study developed norcantharidin-loaded liposomes (NCTD-LPs) to prolong tumor vascular normalization in 4T1 tumor-bearing BALB/c mice, thereby alleviating hypoxia and enhancing radiotherapy efficacy. NCTD-LPs were synthesized via thin-film dispersion and characterized for particle size (140.94 ± 13.23 nm), zeta potential (29.54 ± 2.60 mV), drug-loading capacity (41.81 ± 5.75%), and encapsulation efficiency (15.89% ± 1.28%). In the BALB/c model, dynamic changes in vascular markers (CD31, α-SMA) and hypoxia marker (HIF-1α) were quantified to identify the optimal vascular normalization window. Radiotherapy was administered during this window and compared with conventional regimens to evaluate therapeutic synergy. The coordinated changes in CD31, α-SMA and HIF-1α identified day 10 post-treatment as the optimal period for vascular normalization. The combined NCTD-LPs+radiation group achieved a tumor inhibition rate of 43.60%, significantly surpassing radiation group (18.13%) or NCTD-LPs group (17.24%). Mechanistically, NCTD-LPs stabilized tumor neovasculature, curbed aberrant angiogenesis, and mitigated vascular leakage, collectively improving oxygen perfusion and radiation sensitivity. This study pioneers a liposome-enabled vascular normalization strategy to amplify radiotherapy outcomes, providing a translatable paradigm for combinatorial oncology therapies.
研究领域:
肿瘤学
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药剂学
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放射生物学
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DOI
PubMed
高影响因子
Molecular & Cellular Toxicology
·
2022
·Vol. 19
·期 3
·551-564
·
IF 1.718
Cheng Weina,Chen Qihong,Wang Xiaoning,Liu Liu,Li Xiaofei,Duan Cancan,Zhang Jianyong
Background Norcantharidin (NCTD) has multiple antitumor effects. However, NCTD can induce significant hepatotoxicity and the mechanism of hepatotoxicity is not clear for now. Objective This study aimed to explore the hepatotoxicity of NCTD in rat by ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight (Q-TOF)-MS (UPLC/Q-TOF-MS) metabolomics. Results Serum biochemical indices including alanine aminotransferase (ALT) and total bilirubin (T-BIL) were significantly increased. Histopathological and ultrastructure results revealed that hepatocytes were damaged. Furthermore, the metabolomics results showed that 11 metabolites in serum and 8 metabolites in liver were differential metabolites for NCTD hepatotoxicity. Four metabolic pathways including the sphingolipid metabolism, purine metabolism, arachidonic acid metabolism, and glycerophospholipid metabolism were the key metabolic pathways related to NCTD hepatotoxicity. Conclusion The metabolomics analysis in this study reveal new clues on the hepatotoxicity mechanism of NCTD in rats. These findings have potential applications in the toxicity study of NCTD.
研究领域:
药理学
·
毒理学
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代谢组学
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DOI
高影响因子
TISSUE & CELL
·
2026
·
IF 3.1
Chen Chen,Qin Yu,Chen Xi,Minjuan Xie,Yinjie Jiang,Jie Zhou
Norcantharidin (NCTD) induces nephrotoxicity via mitochondria-dependent apoptosis. • The nephrotoxicity of NCTD involves inhibition of the ATF4/CTH/H 2 S pathway. • NCTD suppresses ATF4-driven CTH expression, reducing H 2 S production. • NCTD reduces H 2 S, impairing Drp1 S-sulfhydration and mitochondrial function. • ATF4, CTH, and H 2 S are potential therapeutic targets for NCTD-induced kidney injury. Norcantharidin serves as a therapeutic agent in the clinical care of malignant neoplasms. However, recent safety alerts issued in China in June 2025 highlighted its association with renal injury. Given that the mechanisms underlying NCTD-induced nephrotoxicity have yet to be completely defined, this work was designed to explore the impact of the ATF4/CTH/H 2 S pathway on nephrotoxicity triggered by NCTD. Our data revealed that exposure to NCTD triggered mitochondria-dependent apoptosis in renal cells, alongside decreased H 2 S levels, ROS accumulation, compromised mitochondrial integrity, and caspase-3 activation. Mechanistically, NCTD inhibited both ATF4 protein levels and its transcriptional function, resulting in downregulation of CTH and a subsequent reduction in H 2 S production. H 2 S deficiency impaired S-sulfhydration of Drp1, enhanced the Drp1-VDAC1 interaction, promoted mPTP opening, and ultimately triggered apoptosis. H 2 S supplementation rescued these defects by restoring Drp1 S-sulfhydration, but this protective effect was completely abolished by DTT, confirming the specificity of S-sulfhydration. Furthermore, overexpression of ATF4 or CTH alleviated NCTD-triggered apoptosis via H 2 S restoration, whereas knockdown of ATF4 or CTH exacerbated cytotoxicity. Critically, CTH knockdown abolished the protective effect of ATF4 overexpression, while CTH overexpression remained functional independently of ATF4. In conclusion, our findings established that NCTD induced nephrotoxicity primarily through the inhibition of the ATF4/CTH/H 2 S axis, which disrupted Drp1-mediated mitochondrial homeostasis. These results identified H 2 S restoration as a promising therapeutic strategy to mitigate NCTD-induced kidney injury.
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高影响因子
LIFE SCIENCES
·
2021
·
IF 5.037
Rui Huang,Qixia Yang,Tiantian Wang
Aims Norcantharidin (NCTD) exhibits antitumor, anti-inflammatory, and anti-fibrosis properties, which makes NCTD an attractive candidate for the treatment of pathological scars. This study was designed to investigate the potential effects of NCTD on fibroblast proliferation and explore the underlying mechanisms. Materials and methods First, cell viability and cell apoptosis were evaluated to determine the effects of NCTD on human skin fibroblasts, at 10, 50, and 100 μM. To explore the mechanism, bioinformatics analyses, chromatin immunoprecipitation, RNA immunoprecipitation, and RNA pulldown assays, and luciferase reporter assays were performed to verify the relationships among NCTD, signal transducer and activator of transcription 3 (STAT3), annexin A2 pseudogene 2 (ANXA2P2), and ubiquitin-associated protein 2-like (UBAP2L) mRNA in fibroblasts. Loss-of-function experiments were performed to investigate the roles played by STAT3, ANXA2P2, and UBAP2L in the proliferation and apoptosis of fibroblasts. Key findings We found that NCTD administration induced fibroblast apoptosis and inhibited fibroblast proliferation in a dose-dependent manner. Mechanistically, NCTD inhibited ANXA2P2 transcription through the inhibition of STAT3 phosphorylation. Subsequently, ANXA2P2 was found to enhance the physical interaction between UBAP2L mRNA and lin-28 homolog B (LIN28B), which increased the stability and levels of UBAP2L mRNA. Loss-of-function assays demonstrated that ANXA2P2 and UBAP2L knockdown induced fibroblast apoptosis and suppressed fibroblast proliferation. Significance In conclusion, we confirmed that NCTD inhibits fibroblast proliferation by inhibiting the STAT3/ANXA2P2/UBAP2L axis, which suggested that NCTD could represent a new candidate for the treatment of pathological scars.
研究领域:
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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病理学
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2025
·
IF 8.1
Yilin Xu,Min Wang,Jing Wu,Manshu Zou,Donghai Wu,Jing Gong,Pingjie Wang,Hong Yan,Xinhua Xia
Liver cancer is a common malignancy in the world, and its incidence and mortality rate are increasing year by year. The disease has a short course and a high mortality rate, posing a serious threat to humanity and health. The objective of this study is to create novel liver-targeted nanoparticles as a potential treatment for liver cancer. The aptamer (APS613-1) modified redox-sensitive norcantharidin solid lipid nanoparticles (Apt-PEG2000-ss-NCTD-SLNs) were prepared by emulsified ultrasonic dispersion method and characterized. The tumor targeting, antitumor effect and safety of the nanoparticles were investigated and evaluated in vitro and in vivo. The particle size of Apt-PEG2000-ss-NCTD-SLNs was 87.95 ± 3.32 nm, and the encapsulation efficiency was about 80.74 ± 2.36%, which had good biocompatibility. The results of in vitro experiments showed that, compared with unmodified solid lipid nanoparticles (NCTD-SLNs), Apt-PEG2000-ss-NCTD-SLNs had better targeting for liver tumor cells, and a stronger ability to inhibit cell proliferation and migration, as well as promote cell apoptosis. The in vivo results revealed that Apt-PEG2000-ss-NCTD-SLNs demonstrated good safety and anti-tumor efficacy, and its mechanism was achieved through the inhibition of cell proliferation and induction of apoptosis. The functionalized nanoparticles modified by aptamer APS613-1 can be used for the liver-targeted delivery of antitumor drugs for the treatment of liver cancer, and Apt-PEG2000-ss-NCTD-SLN is a potential drug for the treatment of liver cancer.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2013
·
IF 2.596
Xiaofen Xu,Yanggong Li,Yuanyuan Shen,Shengrong Guo
Norcantharidin-conjugated chitosan conjugates (NCTD-CSs) with different degrees of substitution ( DS , 60.2% and 97.9%) were synthesized and characterized by 1 H NMR, FT-IR, and XRD. In comparison with CS, the NCTD-CSs had lower crystallinity and better water solubility. Less than 6% NCTD was released from the NCTD-CSs through the hydrolysis of ester bonds in phosphate-buffered solution (PBS, pH 5.0 and 7.4) within 16 days, showing sustained drug release characteristic. The result of cytoxicity study showed that the NCTD-CSs were cytotoxic to MGC80-3 cells and their cytotoxicity was lower than that of NCTD. Fluorescence microscope and flow cytometry analysis demonstrated that the amount of the NCTD-CSs uptaken by MGC80-3 cells increased as incubation time. Confocal microscopy study showed that the NCTD-CSs were internalized into cells by endocytosis and mainly localized in lysosomes within 24 h. It was found that the NCTD-CSs arrested MGC80-3 cell cycle at G2/M phase and induced cell death via cell apoptosis similarly to NCTD. These results indicated that the NCTD-CSs might be an efficient NCTD delivery system for cancer therapy.
研究领域:
药学
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肿瘤学
·
材料科学
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DOI
PubMed
高影响因子
DALTON TRANSACTIONS
·
2022
·Vol. 51
·期 14
·5624-5634
·
IF 4.569
Jia Wang,Xiange Huang,Hegen Li,Deyue Yan,Wei Huang
Here two Zn(II) coordination polymers [Zn20(DMCA)12]O12 (DMCA = demethylcantharic acid, DMCA-Zn1) and [Zn(DMCA)](H2O)2 (DMCA-Zn2) are synthesized from a broad-spectrum anticancer drug norcantharidin (NCTD) and Zn(NO3)2·6H2O under solvothermal conditions. By mechanical grinding with a biocompatible polymeric surfactant F127, ultrasonic treatment and filtration, DMCA-Zn1 and DMCA-Zn2 can be transformed into stable nanoparticles (DMCA-Zn1 NPs and DMCA-Zn2 NPs) suspended in water with average diameters of around 190 nm and 162 nm for drug delivery. The in vitro evaluation indicates that DMCA-Zn1 NPs and DMCA-Zn2 NPs can enter into HepG2 and Hep3B cancer cells via endocytosis and inhibit their proliferation. Meanwhile they exhibit relatively low toxicity to L927 normal cells. The in vivo evaluation confirms that DMCA-Zn1 NPs and DMCA-Zn2 NPs can more effectively inhibit the growth of Hep3B tumors with relatively few side effects compared with free NCTD. This approach can be extended to other anticancer drugs to construct nanodrug delivery systems for cancer treatment.
研究领域:
化学
·
材料科学
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药理学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Xiaohuan Guo,Bingbing Cai,Qi Fang,Yanyan Chen,Yuzhu Zhou,Zhixing Liang,Changchun Wen,Yan-Cheng Liu,Hong Liang
The high level of glutathione (GSH) in tumor cells can consume reactive oxygen species (ROS), seriously affecting the efficacy of chemodynamic therapy (CDT). Although it took a great deal of effort, developing a tumor-specific CDT that efficiently depletes GSH remains a formidable challenge. Herein, we propose a pH-responsive nanocatalyst containing the active molecule norcantharidin (NCTD) and Cu 2+ for dual GSH depletion, achieving efficient GSH depletion. Due to the weakly acidic tumor microenvironment (TME), the catalyst releases NCTD and Cu 2+ in a pH-responsive manner for the synergistic therapy of chemotherapy (CT) and CDT. Both components consume GSH and subsequently produce ROS, reducing the antioxidant capacity of cancer cells while increasing oxidative stress. This disrupts cellular redox homeostasis, leading to mitochondrial dysfunction and inducing tumor cell apoptosis. This work not only develops nanomaterials with dual GSH depletion capabilities for high-efficiency CDT but also achieves synergistic CT and CDT tumor therapy with the addition of NCTD, an active ingredient of traditional Chinese medicine.
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PubMed
高影响因子
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
·
2017
·
IF 1.86
Liya Zeng,Yalin Zhang
This study focused on developing a self-nanoemulsifying drug delivery system (SNEDDS) containing bioactive surfactants under an efficient screening approach for overcoming problems associated with the delivery of norcantharidin (NCTD), a high dose chemotherapy agent having pH dependent solubility. Preliminary screening was implemented to select proper components combination. Besides the solubility of NCTD in the oil phase, emulsifying efficiency, droplet size and size distribution were also employed to select components of the SNEDDS. Moreover, the influence of surfactant and co-surfactant on the interfacial tension and droplets of nanoemulsions were investigated to further understand the mechanism of spontaneous emulsification. Co-surfactant addition promoted the emulsification via reducing the water/oil interfacial tension and viscosity. Ternary phase diagrams were constructed to investigate the phase behavior and designate the optimum systems. The alternative formulations were characterized for cloud point, dilution robustness, droplet size, polydispersity index (PDI) and transmission electron microscopy (TEM). In vitro dissolution study showed that the dissolution rate of optimized formulation (NCTD 10 mg/g, EO 50 wt.%, Cremophor EL 35 wt.%, ethylene glycol 15 wt.%) was slower than drug suspension under the same conditions, confirming that the developed SNEDDS formulation would exhibit sustained release potential.
研究领域:
药学
·
药物递送系统
·
药剂学
·
纳米技术
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产品关联
DOI
PubMed
高影响因子
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