NEW JOURNAL OF CHEMISTRY
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2024
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IF 2.7
Xinyu Wang,Hui Zhang,Ping Bai,Jinjin Shi,Qiaoyun Li,Wei Liu
Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in pre-clinical studies. MLN4924, as a small molecule inhibitor of the neddylation, has been found to effectively inhibit the growth of a variety of cancer cells. However, its clinical application still faces some major challenges in terms of the poor water solubility, biological stability, poor targeting, and rapid clearance from the body. Herein, we developed a biomimetic nanovesicle platform (named P-PAM/MLN) by ultrasonically storing MLN4924-loaded polyamidoamine (PAMAM) dendrimer into platelet membrane vesicles (PMVs) for tumor therapy. Benefiting from PMVs-based camouflage, P-PAM/MLN exhibited enhanced tumor affinity, avoiding the off-target toxicity of MLN4924. Moreover, P-PAM/MLN could selectively release MLN4924 in response to the acidic microenvironment of lysosomal compartments via "Proton Sponge" effect. Conse-quently, the biomimetic nanovesicles could remarkably inhibit tumor progression with negligible toxicity. In terms of significance, the nanovesicles provide a precisely targeted delivery platform for delivering small molecule drugs to the tumor tissue as well as an effective reference for the combined application of nanocarriers and clinical drugs.
研究领域:
药学
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肿瘤学
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纳米医学
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2023
·Vol. 28
·期 1
·1-10
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IF 4.2
Gu Shanshan,Lin Chen,Li Yanguo,Wei Zhengyu,cao Bing,Shen Zhisen,Deng Hongxia
Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin–RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL CYCLE
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2018
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IF 3.304
Xiaoyu Chen,Danrui Cui,Yanli Bi,Jianfeng Shu,Xiufang Xiong,Yongchao Zhao
Breast cancer is a common type of cancer among female cancer patients and the main cause of cancer-related deaths. During the last decades, targeted therapies for breast cancer have been rapidly developing. Among them, MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, has performed antitumor activity by inactivating the cullin-RING ligases and causing the accumulation of their substrates to induce apoptosis in a number of studies. In this study, we found that MLN4924 activates the AKT pathway in both HER2-positive and triple-negative breast cancer (TNBC) cell lines. Given that AKT signaling is responsible for tumor progression and drug resistance in some types of cancers, we hypothesized that the AKT inhibitor may synergistically enhance the tumor suppression capability in breast cancer by MLN4924. To demonstrate the sensitizing effect, MK-2206 was chosen as the adjuvant treatment, and cell growth, migration and apoptosis were detected. The results showed that MLN4924 treatment inhibited cell growth and migration and induced apoptosis in both SK-BR3 and MDA-MB231 breast cancer cell lines. More importantly, the combined treatment of MLN4924 and MK-2206 indeed caused stronger cytotoxicity and inhibition of migration and a much higher induction of apoptosis compared with MLN4924 treatment alone. Our study provides the proof-of-concept evidence for strategic drug combination of MLN4924 with an AKT inhibitor for maximal killing of breast cancer cells via the enhancement of apoptosis.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Yueyang Guo,Zhuang Hu,Linyue Bai,Yanjun Tang,Jingyi Hu,Qianqian Zhang,Jiali Liu,Siqi Feng
Gastric cancer, a leading cause of cancer-related mortality, has a median survival of just 15 months in advanced stages and currently lacks effective treatment options. Neddylation blockade is a promising therapeutic strategy, yet its clinical application faces challenge with the emergence of drug resistance. Currently, the underlying mechanisms behind the drug resistance are not fully understood. Our study uncovers the link between MLN4924-induced metabolic reprogramming and its antitumor efficacy in gastric cancer cells. We first demonstrated that MLN4924, a neddylation blocker, has multiple effects on gastric cancer cell growth, notably inducing mitochondrial damage. Untargeted metabolomic analysis revealed that MLN4924 enhances glucose utilization in gastric cancer cells in a concentration-dependent manner. Mechanistically, MLN4924 reduces the neddylation of cullin2, thereby inhibiting the degradation of HIF-1α. This leads to the accumulation of HIF-1α, which upregulates GLUT1 levels and facilitates increased glucose uptake. This metabolic adaptation allows gastric cancer cells to maintain their energy supply despite mitochondrial impairment. Based on the increased glucose dependency following neddylation inhibition by MLN4924, we propose a co-targeting strategy with GLUT1 inhibition, which significantly improves therapeutic efficacy in vitro and in vivo models without safety risks. This dual-targeting approach represents a potent new strategy for gastric cancer treatment.
研究领域:
肿瘤学
·
代谢组学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Anwei Zhou,Kerong Chen,Ya Gao,Xinyuan Zhou,Zihan Tian,Weiwei Chen,Yurui Xu,Zhuo Chen,Xinghai Ning
Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit limited potential to balance immune response and overproduction of inflammatory cytokines, leading to poor therapeutic outcomes. Herein, a smart bioengineered neutrophil, Extinguisher, composed of live neutrophils encapsulating the liposome formulation of NF-κB suppressor MLN4924 and STING inhibitor H-151 (Lip@MH), is developed for alleviating the hyperinflammatory cytokine storm. Extinguisher inherits motility and chemotaxis characteristics of neutrophils, allowing for the specific delivery and sustained release of Lip@MH within inflamed tissues. Subsequently, Lip@MH effectively transports anti-inflammatory agents into macrophages and synergistically inhibits inflammatory pathways of NF-κB and STING, leading to decreased production of cytokines. In vivo studies demonstrate that Extinguisher not only selectively accumulates at the site of pneumonia caused by Pseudomonas aeruginosa-induced acute lung injury but inhibits the production of inflammatory factors through regulating NF-κB/STING signaling pathways, thereby effectively calming cytokine storm. Importantly, Extinguisher significantly improves therapeutic benefits and survival in mice with acute pneumonia. Therefore, Extinguisher represents an appropriate combination of cell therapy and immunoregulation for cytokine storm intervention and may bring insights into the treatment of COVID-19 pneumonia.
研究领域:
免疫学
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生物技术
·
药学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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