Oncotarget
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2016
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IF 5.008
Lian Chen,Hengmin Cui,Jing Fang,Huidan Deng,Ping Kuang,Hongrui Guo,Xun Wang,Ling Zhao
Glutamine provides cancer cells with the energy required to synthesize macromolecules. Methods which block glutamine metabolism in treatment of breast cancer inhibit oncogenic transformation and tumor growth. We investigated whether inhibiting glutamine metabolism produces effects that are synergistic with those produced by drugs which damage DNA in triple-negative breast cancer cells. HCC1937 and BT-549 breast cancer cells were co-treated with either cisplatin or etoposide in combination with BPTES (a specific inhibitor of glutaminase 1) or exposure to a glutamine-free medium, and the cell proliferation and cell apoptosis were measured by flow cytometry, immunoblotting studies, and CCK-8 assays. The results showed that both glutamine deprivation and BPTES pretreatments increased the toxic effects of cisplatin and etoposide on HCC1937 cells, as demonstrated by their reduced proliferation, increased expression of apoptosis-related proteins (cleaved-PARP, cleaved-caspase 9, and cleaved-caspase 3) and decreased Bcl-2/BAX ratio. However, in BT-549 cells, glutamine deprivation and BPTES treatment increased etoposide-induced apoptosis only when used with higher concentrations of etoposide, and the effect on cisplatin-induced apoptosis was minimal. These results suggest that the anti-cancer effects produced by a combined approach of inhibiting glutamine metabolism and administering common chemotherapeutic agents correlate with the tumor cell type and specific drugs being administered.
研究领域:
肿瘤学
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
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2022
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IF 10.761
Zhenxiang Fu,Huiping Du,Siyu Meng,Mengjiao Yao,Pan Zhao,Xiang Li,Xinmin Zheng,Zhang Yuan,Hui Yang,Kaiyong Cai,Liangliang Dai
The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, [email protected] @B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.
研究领域:
肿瘤学
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药学
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纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
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2024
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IF 14.3
Qian Cheng,Yuzhe Chen,Danyi Zou,Qilin Li,Xiaolei Shi,Qushuhua Qin,Miaodeng Liu,Lin Wang,Zheng Wang
The anti-tumor efficacy of current pharmacotherapy is severely hampered due to the adaptive evolution of tumors, urgently needing effective therapeutic strategies capable of breaking such adaptability. Metabolic reprogramming, as an adaptive survival mechanism, is closely related to therapy resistance of tumors. Colorectal cancer (CRC) cells exhibit a high energy dependency that is sustained by an adaptive metabolic conversion between glucose and glutamine, helping tumor cells to withstand nutrient-deficient microenvironments and various treatments. We discover that transition metal vanadium (V) effectively inhibits glucose metabolism in CRC and synergizes with glutaminase inhibitors (BPTES) to disrupt CRC's energy dependency. Thus, a dual energy metabolism suppression nanosystem (VSi-BP@HA) is engineered by loading BPTES into V-doped hollow mesoporous silica nanoparticles. This nanosystem effectively dampens CRC energy metabolism, eradicating 33% of tumors in mice. Strikingly, the cell biological and preclinical model datasets provide compelling evidence showing that VSi-BP@HA not only reverses CRC cells chemo-resistance but also drastically potentiates anti-PD1 immunotherapy. Therefore, this nanosystem provides not only a promising approach to suppress CRC, but also a potential adjunct tool for enhancing chemotherapy and immunotherapy.
研究领域:
肿瘤学
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药理学
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纳米技术
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免疫学
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癌症代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNOLOGY LETTERS
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2025
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IF 2.8
Xing Chen,Lixiang Li,Yan Deng,Juan Liao,Hui Meng,Limei Liang,Jie Hu,Dongwei Xie,Guizi Liang
(1) Background Metabolic abnormalities and immune inflammation are key elements within pathogenesis of pulmonary arterial hypertension (PAH). And in PAH patients, aberrant glutamine metabolism has been observed; however, the function of glutaminase 1 (GLS1) in macrophage is still unknown. So we aims to investigate GLS1′s impact upon macrophages in PAH. (2) Methods We firstly constructed an monocrotaline (MCT)-induced PAH rat model. Briefly, the PAH rats were treated with the GLS1 inhibitor BPTES, and various index were evaluated, including hemodynamics, right ventricular function, pulmonary vascular remodeling, macrophage markers, and glutamine metabolism. After that, we polarized bone marrow-derived macrophages (BMDMs) into M1 phenotype and then subjected to BPTES intervention. Finally, we assessed macrophage phenotype, inflammatory markers, and glutamine metabolism indicators, along with the impact of BMDM supernatant on the behavior of pulmonary arterial smooth muscle cells (PASMCs). (3) Results : GLS1 was significantly upregulated in both PAH patients and rats. Treatment with the GLS1 inhibitor BPTES markedly improved pulmonary arterial pressure, right ventricular function, and pulmonary vascular remodeling in PAH rats, while inhibiting M1 macrophage polarization, NLRP3 activation, and the release of pro-inflammatory cytokines. This, in turn, alleviated the proliferation and migration of PASMCs induced by inflammatory stimuli. (4) Conclusion : We propose that targeting GLS1 to reduce M1 macrophage polarization and inflammatory responses may represent a promising therapeutic approach for PAH.
研究领域:
心血管疾病
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免疫学
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药理学
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细胞生物学
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代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2022
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IF 10.633
Xuzi Cai,Si Shi,Gui Chen,Min Zhong,Yuanyuan Yang,Ziyi Mai,Yang Tian,Jinxiu Tan,Lijuan He,Chunhui Cui,Zhiqiang Yu,Xuefeng Wang
Platinum-based chemotherapy is a first-line therapeutic regimen against ovarian cancer (OC); however, the therapeutic potential is always reduced by glutamine metabolism. Herein, a valid strategy of inhibiting glutamine metabolism was proposed to cause tumor starvation and chemosensitization . Specifically, reactive oxygen species-responsive liposomes were developed to co-deliver cisplatin (CDDP) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [ [email protected] LPs]. The [email protected] LPs induced effective tumor cell starvation and significantly sensitized OC cells to CDDP by reducing glutathione generation to prevent CDDP detoxification, suppressing ATP production to avoid CDDP efflux, hindering nucleotide synthesis to aggravate DNA damage induced by CDDP, and blocking mammalian target of rapamycin (mTOR) signaling to promote cell apoptosis. More importantly, [email protected] LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs. Statement of significance This work proposed a valid strategy of inhibiting glutamine metabolism to cause tumor starvation and chemosensitization. Specifically, ROS-responsive liposomes were developed to co-deliver cisplatin CDDP and BPTES [ [email protected] LPs]. The [email protected] LPs induced effective tumor cell starvation and significantly sensitized OC cells to cisplatin by reducing glutathione generation to prevent cisplatin detoxification, suppressing ATP production to avoid cisplatin efflux, hindering nucleotide synthesis to aggravate DNA damage induced by cisplatin, and blocking mTOR signaling to promote cell apoptosis. More importantly, [email protected] LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs.
研究领域:
肿瘤学
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药学
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生物医学工程
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化疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
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2023
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IF 8.2
Cancan Yu,Ningning Wang,Xiangwu Chen,Yue Jiang,Yuxia Luan,Wen Qin,Wenxiu He
“Glutamine addiction” is a unique feature of triple negative breast cancer (TNBC), which has a higher demand for glutamine and is more susceptible to glutamine depletion. Glutamine can be hydrolyzed to glutamate by glutaminase (GLS) for synthesis of glutathione (GSH), which is an important downstream of glutamine metabolic pathways in accelerating TNBC proliferation. Consequently, glutamine metabolic intervention suggests potential therapeutic effects against TNBC. However, the effects of GLS inhibitors are hindered by glutamine resistance and their own instability and insolubility. Therefore, it is of great interest to harmonize glutamine metabolic intervention for an amplified TNBC therapy. Unfortunately, such nanoplatform has not been realized. Herein, we reported a self-assembly nanoplatform (BCH NPs) with a core of the GLS inhibitor Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and photosensitizer Chlorin e6 (Ce6) and a shell of human serum albumin (HSA), enabling effective harmonization of glutamine metabolic intervention for TNBC therapy. BPTES inhibited the activity of GLS to block the glutamine metabolic pathways, thereby inhibiting the production of GSH to amplify the photodynamic effect of Ce6. While Ce6 not only directly killed tumor cells by producing excessive reactive oxygen species (ROS), but also deplete GSH to destroy redox balance, thus enhancing the effects of BPTES when glutamine resistance occurred. BCH NPs effectively eradicated TNBC tumor and suppressed tumor metastasis with favorable biocompatibility. Our work provides a new insight for photodynamic-mediated glutamine metabolic intervention against TNBC.
研究领域:
癌症生物学
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药学
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纳米技术
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
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2023
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IF 9.7
Jie Zhang,Liwen Wei,Xiaocao Ma,Jingguo Wang,Siping Liang,Kang Chen,Minhao Wu,Li Niu,Yuanqing Zhang
Metabolic dysregulation contributes not only to cancer development but also to a tumor immune microenvironment (TIME), which poses great challenges to chemo- and immunotherapy. Targeting metabolic reprogramming has recently emerged as a promising strategy for cancer treatment, but the lethality against solid tumors appears to be fairly restricted, partially due to the poor solubility of small molecule drugs. Herein, we construct a versatile biomimetic nanoplatform (referred to as HM-BPT) employing pH-sensitive tumor-tropism hybrid membrane-coated Manganese oxide (MnO 2 ) nanoparticles for the delivery of BPTES, a glutamine metabolism inhibitor. Basically, hybrid membranes consisting of mesenchymal stem cell membranes (MSCm) and pH-sensitive liposomes (pSL) enable the biomimetic nanoplatform to target TME and escape from endo/lysosomes after endocytosis . The results reveal that HM-BPT treatment leads to remarkable tumor inhibition, cytotoxic T lymphocyte (CTL) infiltration , as well as M1 phenotype repolarization and stimulator of IFN genes (STING) pathway activation in macrophages in a 4T1 xenograft model. Furthermore, glutathione (GSH) depletion and oxygen (O 2 ) supply synergistically ameliorate the immunosuppressive status of the TME, boosting potent antitumor immune responses. Overall, our study explores an integrated therapeutic platform for TME reprogramming and immune activation, offering tremendous promise for cancer combination therapy. Statement of significance Metabolic abnormalities and the tumor immune microenvironment (TIME) lead to hyporesponsiveness to conventional therapies, ultimately resulting in refractory malignancies. In the current work, a biomimetic nanoplatform (HM-BPT) was developed for TME metabolic reprogramming in favor of immunotherapy. Particularly, hybrid membrane camouflage endowed the nanoplatform with TME targeting, endo/lysosomal escape, and sensitive release properties. The impact of hybrid membrane fusion ratio on cellular uptake and cell viability was explored, yielding beneficial references for the future development of bioactive nanomaterials . Intravenous administration of HM-BPT substantially relieved tumor burden and restored innate and acquired immune activation in 4T1 xenograft models. In conclusion, the created HM-BPT system has the potential to be a promising nanoplatform for combining cancer therapies.
研究领域:
癌症治疗
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免疫学
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纳米技术
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药理学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）