CELL RESEARCH
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2023
·Vol. 33
·期 12
·923-939
·
IF 44.1
Liu Rui,Zeng Lin-Wen,Li Hui-Fang,Shi Jun-Ge,Zhong Bo,Shu Hong-Bing,Li Shu
Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γ c ). PD-1 ligation also activates SHP2, which dephosphorylates γ c Y357 , leading to impairment of γ c family cytokine-triggered signaling. Conversely, PD-1 blockade restores γ c level and activity, thereby sensitizing CD8 + T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γ c family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.
研究领域:
免疫学
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肿瘤学
·
分子生物学
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DOI
PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 6
·667
·
IF 6
Wanqian Li,Yanru Feng,Zhe Feng,Li Wang,Malcolm Whiteway,Hui Lu,Yuanying Jiang
Fluconazole (FLC) is extensively employed for the prophylaxis and treatment of invasive fungal infections (IFIs). However, the fungistatic nature of FLC renders pathogenic fungi capable of developing tolerance towards it. Consequently, converting FLC into a fungicidal agent using adjuvants assumes significance to circumvent FLC resistance and the perpetuation of fungal infections. This drug repurposing study has successfully identified pitavastatin calcium (PIT) as a promising adjuvant for enhancing the fungicidal activity of FLC from a comprehensive library of 2372 FDA-approved drugs. PIT could render FLC fungicidal even at concentrations as low as 1 μM. The median lethal dose (LD50) of PIT was determined to be 103.6 mg/kg. We have discovered that PIT achieves its synergistic effect by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby impeding ubiquinone biosynthesis, inducing reactive oxygen species (ROS) generation, triggering apoptosis, and disrupting Golgi function. We employed aCandida albicansstrain that demonstrated a notable tolerance to FLC to infect mice and found that PIT effectively augmented the antifungal efficacy of FLC against IFIs. This study is an illustrative example of how FDA-approved drugs can effectively eliminate fungal tolerance to FLC.
研究领域:
药理学
·
微生物学
·
传染病学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Yuan-yuan Zhai,Qiang Wang,Qi-yao Nong,Mei-yu Gao,Ying Zhang,Qin-wen Xiao,Yuan Tian,Zun-jian Zhang,Feng-guo Xu,Pei Zhang
Multidrug resistance (MDR) is a significant challenge in cancer treatment, with limited effective strategies available. Neuropilin-1 (NRP1) is emerging as a potential therapeutic target for overcoming drug resistance, but its role in MDR and the identification of potential inhibitors require further exploration. In this study, we investigated the role of NRP1 in MDR and identifies potential inhibitors targeting NRP1. Elevated NRP1 expression was observed in oxaliplatin (OXP)-resistant HCT116 (HCT116/L) and cisplatin (DDP)-resistant A549 cells (A549/DDP). Virtual screening and biological assays identified pitavastatin (Ptv) as a potent NRP1 inhibitor that restored chemosensitivity in resistant cells both in vitro and in vivo . Mechanistic studies revealed that Ptv directly binds to NRP1, promotes degradation of Zinc finger X-chromosomal protein (ZFX), and disrupts the NRP1-ZFX axis to reverse MDR. This study provides promising prospects for targeting the NRP1-ZFX axis as a therapeutic strategy for MDR and highlights the potential clinical application of Ptv in diseases involving NRP1.
研究领域:
癌症生物学
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药理学
·
分子生物学
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肿瘤学
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药物研发
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2026
·
IF 4.9
Shuang Lu,Shuo Wang,Xueying Tang,Yangxu Gui,Jiawei Lian,Xinrong Liu,Yanzhi Song,Yihui Deng
Atherosclerotic cardiovascular disease (ASCVD) poses a severe threat to human health, and the global prevalence of atherosclerosis-related diseases continues to rise, necessitating urgent exploration of novel strategies. Inspired by the close links between tumors and atherosclerosis (AS), as well as the clinical reality of their comorbidity, the present study encapsulated pitavastatin within liposomes and modified them with sialic acid-cholesterol (SA-CH) to achieve targeted drug delivery via peripheral blood neutrophils (PBNs). Compared to oral pitavastatin administration, sialic acid-modified pitavastatin liposomes (PIT-SAL) demonstrated superior efficacy in attenuating disease progression in atherosclerotic mice, with sustained therapeutic effects even after treatment cessation, suggesting the potential for eradication of AS. Notably, PIT-SAL additionally exhibited antitumor potential by effectively reducing tumoral cholesterol accumulation while enhancing T-cell infiltration. Collectively, our preliminary findings highlight the great translational potential of PIT-SAL as a targeted therapy for both AS and tumors, offering a potential breakthrough in managing these interconnected diseases.
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DOI
PubMed
高影响因子
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