BIOCHEMICAL PHARMACOLOGY
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2023
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IF 5.8
Xiaoxiang Mo,Xiaoju Shen,Xiaocheng Mo,Fei Yu,Weidan Tan,Zhihua Deng,Jingchuan He,Zhuo Luo,Zhiquan Chen,Jie Yang
Small cell lung cancer (SCLC) is the most malignant lung cancer with rapid growth and early metastasis, but still lacks effective targeted therapies to improve the prognosis. Here, we demonstrated that a novel oncogenic protein, cell migration inducing hyaluronic binding protein (CEMIP), was robustly overexpressed in SCLC tissues than that in noncancerous tissues and high expression of CEMIP predicted poor outcomes in clinical specimens and in large sample size cohorts from public databases (GEPIA 2 and CPTAC). Liquid chromatography mass spectrometry (LC-MS) and in vitro/in vivo functional assays indicated that CEMIP contributed to the proliferation by increasing glutamine consumption and their metabolites (glutamate and glutathione) levels in SCLC cells. Moreover, the addition of a GLS1 inhibitor CB-839 dramatically reduced CEMIP-induced SCLC cell proliferation . Mechanistically, beyond as a scaffold protein , CEMIP facilitates glutamine-dependent cell proliferation through inhibiting c-Myc ubiquitination and increasing c-Myc stabilization and nuclear accumulation via hindering the interaction between FBXW7 (a E3 ubiquitin ligase) and its target substrate c-Myc. Taken together, our findings reveal a novel oncogenic role of CEMIP in sustaining SCLC growth via FBXW7/c-Myc-dependent axis, and provide new evidence that inhibition of CEMIP might be a potential therapeutic strategy for the treatment of SCLC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
Small
·
2023
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IF 13.3
Zhiyan Li,Xianghui Li,Yanjun Lu,Xudong Zhu,Wenxuan Zheng,Kai Chen,Song Liu,Jinhui Wu,Wenxian Guan
Photodynamic therapy (PDT) has promising applications. However, the lethal function of reactive oxygen species (ROS) produced during PDT is typically limited. This restriction is induced by oxygen shortage in the tumor microenvironment due to tumor cell hypermetabolism and reductive chemicals overexpression in tumor tissues. Glutamine (Gln) metabolism is crucial for malignancy development and is closely associated with redox. Herein, a novel nanoparticle (NP) named IRCB@M is constructed to boost PDT through dual effects. This NP simultaneously blocks aerobic respiration and inhibits cellular reduced substances by blocking the Gln metabolic pathway. Within the nanocomplex, a photosensitizer (IR-780) and a glutaminase inhibitor (CB-839) are self-assembled and then encapsulated by cancer cell membranes for homologous targeting. The Gln metabolism intervention relieves hypoxia and decreases the levels of nicotinamide adenine dinucleotide phosphate (NADPH) as well as reduced glutathione (GSH) in vitro and in vivo, which are the dual amplification effects on the IR-780-mediated lethal PDT. The antitumor effects against gastric cancer are ultimately evoked in vivo, thus offering a novel concept for enhancing PDT and other ROS-dependent therapeutic approaches.
研究领域:
癌症研究
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纳米技术
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治疗学
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生物化学
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DOI
PubMed
高影响因子
ACS Nano
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2022
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IF 18.027
Feng Wu,Yaqian Du,Jiani Yang,Boyang Shao,Zhensheng Mi,Yuanfei Yao,Ying Cui,Fei He,Yanqiao Zhang,Piaoping Yang
The nanocatalytic activity of nanozymes provides a vision for tumor treatment. However, the glutathione (GSH)-related antioxidant defense system (ADS) formed on the basis of excessive GSH in the tumor microenvironment limits its catalytic activity. Here, dendritic mesoporous silica nanoparticles (DMSNs) were employed as nanocarrier; ultrasmall Fe3O4 nanoparticles, Mn2+ ions, and glutaminase inhibitor Telaglenastat (CB-839) were subsequently integrated into large mesopores of DMSNs, forming DMSN/Fe3O4–Mn@CB-839 (DFMC) nanomedicine. This nanomedicine exhibits peroxidase mimicking activities under acidic conditions, which catalyzes the decomposition of hydrogen peroxide (H2O2) into hydroxyl radical (•OH). This also promotes the formation of lipid peroxides, which is required for ferroptosis. Furthermore, this nanomedicine can effectively deplete the existing GSH, thereby enhancing reactive oxygen species (ROS)-mediated tumor catalytic therapy. Moreover, the introduced CB-839 blocks the endogenous synthesis of GSH, further enhancing GSH depletion performance, which reduces the excretion of oxaliplatin (GSH-related resistance) from tumor cells, thereby restoring the chemical sensitivity of oxaliplatin. The dual GSH depletion property significantly weakens the GSH-related ADS and restores the chemical sensitivity of oxaliplatin, leading to the high DFMC-induced apoptosis and ferroptosis of tumor cells. Our developed nanomedicine based on integrated nanotechnology and clinical drug may aid the development of tumor treatment.
研究领域:
纳米技术
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癌症治疗
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药学
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生物医学工程
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Haofan Hu,Shangwu Ning,Furong Liu,Ze Zhang,Weifeng Zeng,Yachong Liu,Zhibin Liao,Hongwei Zhang,Zhanguo Zhang
Hepatocellular carcinoma (HCC) with MYC oncogene amplification remains a serious challenge in clinical practice. Recent advances in comprehensive treatment strategies, particularly the combination of radiotherapy and immunotherapy, offer new hope. To further improve efficacy while lowering radiation doses, nanopharmaceuticals based on high-Z elements have been extensively studied in radio-immunotherapy. In this work, a hafnium-based metal–organic framework (Hf-MOF), UiO-66-Hf(2OH)-CB-839/BSO@HA (UiO-66-Hf(2OH)-C/B@HA), was designed to codeliver telaglenastat (CB-839) and buthionine sulfoximine (BSO), which synergistically inhibited glutamine metabolism and alleviated tumor hypoxia. Further modification with hyaluronic acid (HA) enhanced tumor targeting, ultimately strengthening the efficacy of radiotherapy in MYC-amplified HCC. Beyond increasing reactive oxygen species (ROS) generation, promoting DNA damage, and inducing tumor apoptosis, more importantly, UiO66-Hf(2OH)-C/B@HA triggered immunogenic cell death (ICD), driving the antitumor immune response. Combination with immune checkpoint blockade (ICB) further enhanced the efficacy, accompanied by increased infiltration of T cells with high granzyme B expression (GZMB+ T cells) within the tumor microenvironment (TME). In the orthotopic HCC model, established with MYC-amplified tumor cells, intravenous administration of UiO66-Hf(2OH)-C/B@HA significantly potentiated the efficacy of radio-immunotherapy, resulting in superior tumor regression. In summary, our study provides insights into the design of Hf-MOF for radio-immunotherapy and proposes a promising therapeutic approach for MYC-amplified HCC.
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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免疫学
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DOI
PubMed
高影响因子
Redox Biology
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2025
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IF 11.9
Benjian Gao,Dongning Zheng,Hong Liu,Yu Guo,Yuntao Ye,Zhou Chen,Fengyi Yang,Jie Liu,Guangnian Zhang,Guoying Feng,Yongfa Liu,Qiang Wang,Song Su,Xiaoli Yang,Bo Li
Glutamine addiction represents a metabolic vulnerability in hepatocellular carcinoma (HCC), making glutaminase inhibitor CB-839 therapy a promising approach. However, effective therapeutic strategies are not yet available. In this study, we aim to investigate the potential role of asparagine synthetase (ASNS) as a target for HCC therapy during CB-839 treatment. CB-839 suppressed HCC cell growth, triggered apoptosis, and induced oxidative stress along with the disruption of amino acid metabolism. Moreover, ASNS was induced by CB-839 treatment through the activation of the amino acid response pathway. ASNS was significantly upregulated in HCC tumor tissues and was positively associated with poor prognosis; indeed our results revealed that its overexpression facilitated the proliferation, migration, and invasion of HCC cells. Furthermore, ASNS increased glutaminolysis and glutathione synthesis through reprogramming glutamine metabolism to maintain intracellular redox homeostasis, thereby activating the mTOR pathway that contributed to HCC progression. ASNS knockdown sensitized HCC cells to CB-839 both in vitro and in vivo . Overall, ASNS modulated the sensitivity to CB-839 in HCC through metabolic reprogramming, potentially serving as a biomarker for CB-839 response and a promising therapeutic target for HCC.
研究领域:
癌症生物学
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肝病学
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代谢工程
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药理学
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分子生物学
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肿瘤学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 13.2
Ruo-Yun Zhang,Wei Yue,Yang Xuan,Long Qi,Lin-Lin Guo,Zhen-Zhen Zhu,Ming Yang,Zhang-Jie Pu,Guo-Qiang Li,Xin-Yi Mao,Ding Zhou,Zhao-Wei Zhang
Immunogenic cell death (ICD) attracts significant attention by initiating adaptive immune responses for antitumor immunotherapy. Although ROS is developed to trigger ICD as an inducer, the effect of immunotherapy is compromised by the scavenging of ROS in the immunosuppressive tumor microenvironment. Herein, we report an injectable cascade-amplified ICD nanofiber hydrogel self-assembled from steroid drug prednisolone sodium phosphate (PSP) and calcium chloride for the local delivery of glutaminase inhibitor CB-839 and the sonosensitizer Ce6 (CCPG). ROS is generated by stimulating Ce6 under ultrasound (US), which disrupts the Ca 2+ buffer capacity of mitochondria to induce Ca 2+ influx, thereby triggering ICD to release damage-associated molecular patterns (DAMPs) from dying tumor cells for initiating T cell infiltration. Moreover, ICD induction is further amplified by the glutaminase inhibitor CB-839. CB-839 suppresses glutathione (GSH) synthesis by inhibiting the conversion of glutamine to glutamate as the precursor of GSH, thereby limiting the scavenging of Ce6-generated ROS and enhancing their antitumor and ICD-triggering effects. Additionally, anti-inflammatory PSP suppresses matrix metalloproteinase-2 (MMP-2) expression, resulting in facilitating T cell infiltration. As a consequence, this work highlights a strategy to reprogram immunosuppressive tumor microenvironment via cascade-amplified ICD by inhibiting the scavenging of ROS to maintain Ca 2+ overload, providing new insights for enhancing the efficacy of immunotherapy.
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2026
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IF 7.5
Zhen Li,Fang Li,Wang Song,Chun-mei Long,Xin Zeng,Wen-kai Guo,Bin Chen,Tai-xin Jia,Li Lu
The glutamate (Glu)–glutamine (Gln) cycle between astrocytes and neurons plays a crucial role in maintaining extracellular Glu levels during excitatory neurotoxicity, with glutamine synthetase (GS) and glutaminase (GLS) serving as the key enzymes. Ampelopsin (Amp) exhibits diverse biological and pharmacological activities, including antioxidant, anti-inflammatory, and antitumor effects. Notably, Amp regulates GLS, which is also the established target of CB-839, a potent and specific inhibitor known to suppress tumorigenesis. However, the influence of this effect on neuroprotective effects and Glu homeostasis remains unclear. This study aimed to construct a middle cerebral artery occlusion/reperfusion (MCAO/R) model to assess the effects of Amp and CB-839 on Glu-induced ischemic injury in vivo. Herein, Glu and Gln levels within the Glu–Gln metabolic cycle, and protein levels of GLS, GS, glutamate transporter-1 (GLT-1), and N-methyl- D -aspartate receptor (NMDAR) were analyzed. Immunofluorescence staining was performed to determine the distribution of GLS and GS in brain astrocytes and neurons. Notably, both Amp and CB-839 exerted neuroprotective effects in MCAO/R mice by reducing cerebral infarction area, alleviating brain edema, and improving neurological function. Furthermore, they attenuated neuronal necrosis and mitigated the ischemia-induced damage to neurons and Nissl bodies. In addition, both Amp and CB-839 enhanced GS-mediated Glu-to-Gln conversion in astrocytes by increasing GS activity in the ischemic brain and reducing Glu accumulation through GLT-1 upregulation, which facilitated Glu uptake. In neurons, both Amp and CB-839 inhibited GLS-mediated Gln hydrolysis to Glu by downregulating GLS expression, leading to elevated Gln and decreased Glu levels during cerebral ischemia. Simultaneously, NMDAR expression was reduced, preventing excitatory neurotoxicity driven by excessive glutamatergic signaling. Overall, this study highlights the potential of Amp in providing neuroprotection in mice subjected to transient focal cerebral ischemia by promoting the dynamic Glu homeostasis.
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DOI
PubMed
高影响因子
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