Glutamine addiction activates polyglutamine-based nanocarriers delivering therapeutic siRNAs to orthotopic lung tumor mediated by glutamine transporter SLC1A5

Wang, Cuifeng; Wu, Jia‐Min; Wang, Zhongjuan; Yang, Zeping; Zhi, Liu; Deng, Huihui; Li, Long; Peng, Xiao; Feng, Min

doi:10.1016/j.biomaterials.2018.08.035

Cited by 32 publications

(26 citation statements)

References 52 publications

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“…Glutaminolysis is also directly involved in the regulation of reactive oxygen species (ROS) homeostasis by providing not only precursors glutamate and cysteine for glutathione (GSH) synthesis but also promoting the production of NADPH via glutamate dehydrogenase (GLUD; Altman et al, 2016 ). Many tumor types, such as pancreatic cancer ( Son et al, 2013 ), acute myeloid leukemia (AML; Jacque et al, 2015 ), breast cancer ( Gross et al, 2014 ), and lung cancer ( Wang et al, 2018 ), are particularly dependent on glutamine for proliferation and survival, as glutamine controls oxidative phosphorylation, nucleotide biosynthesis, and redox homeostasis in these cells, and removal of glutamine leads to apoptosis. Recently, it is reported that GLS1, one major isoform of GLS, regulates the stemness properties of HCC, and targeting GLS1 achieved some therapeutic effect against HCC cells ( Li et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Jin

Wang

Zaal

et al. 2020

eLife

111

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The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.

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Section: Introductionmentioning

confidence: 99%

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Jin

Wang

Zaal

et al. 2020

eLife

111

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“…If such transporters can be blocked with appropriately conjugated nanoparticles, cancer cells will undergo nutrient deprivation. This approach has the potential in subjecting cancer cells to growth arrest and/or cell death [ 101 , 104 , 140 , 142 ].…”

Section: Discussionmentioning

confidence: 99%

“…This transporter could be targeted for drug delivery into cancer cells. Wang et al developed glutamine macromolecular analog polyglutamine (PGS) for the siRNA delivery in cancer therapy [ 104 ]. The molecular docking analysis confirmed SLC1A5 has a high affinity towards PGS.…”

Section: Transporter-targeted Ndds For Drug Delivery Into Tumor Cementioning

confidence: 99%

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

Kou

Yao

Zhang

et al. 2020

Cancers

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Nano-devices are recognized as increasingly attractive to deliver therapeutics to target cells. The specificity of this approach can be improved by modifying the surface of the delivery vehicles such that they are recognized by the target cells. In the past, cell-surface receptors were exploited for this purpose, but plasma membrane transporters also hold similar potential. Selective transporters are often highly expressed in biological barriers (e.g., intestinal barrier, blood–brain barrier, and blood–retinal barrier) in a site-specific manner, and play a key role in the vectorial transfer of nutrients. Similarly, selective transporters are also overexpressed in the plasma membrane of specific cell types under pathological states to meet the biological needs demanded by such conditions. Nano-drug delivery systems could be strategically modified to make them recognizable by these transporters to enhance the transfer of drugs across the biological barriers or to selectively expose specific cell types to therapeutic drugs. Here, we provide a comprehensive review and detailed evaluation of the recent advances in the field of transporter-targeted nano-drug delivery systems. We specifically focus on areas related to intestinal absorption, transfer across blood–brain barrier, tumor-cell selective targeting, ocular drug delivery, identification of the transporters appropriate for this purpose, and details of the rationale for the approach.

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“…ASCT2 (SLC1A5) ( Liu et al, 2018 ), a glutamine transporter, was found to be highly expressed in A549 wild-type cells and cisplatin-resistant cells but was negligibly expressed in normal lung fibroblasts ( J. Wu et al, 2018 ). By simulating a polyglutamine delivery system with glutamine macromolecules, SLC1A5 was used to deliver specific therapeutic compounds to glutamine-dependent cancer cells, further sensitizing these cancer cells to cisplatin ( C. Wang et al, 2018a ). The rapid catabolic metabolism of glutamine mediated by the oncogene KRAS continuously enhances the antioxidant capacity of cisplatin-resistant cells, thus enabling them to tolerate cytotoxicity.…”

Section: Amino Acid Metabolism and Cisplatin Resistancementioning

confidence: 99%

The Role of Tumour Metabolism in Cisplatin Resistance

Wang

Zhao

et al. 2021

Front. Mol. Biosci.

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Cisplatin is a chemotherapy drug commonly used in cancer treatment. Tumour cells are more sensitive to cisplatin than normal cells. Cisplatin exerts an antitumour effect by interfering with DNA replication and transcription processes. However, the drug-resistance properties of tumour cells often cause loss of cisplatin efficacy and failure of chemotherapy, leading to tumour progression. Owing to the large amounts of energy and compounds required by tumour cells, metabolic reprogramming plays an important part in the occurrence and development of tumours. The interplay between DNA damage repair and metabolism also has an effect on cisplatin resistance; the molecular changes to glucose metabolism, amino acid metabolism, lipid metabolism, and other metabolic pathways affect the cisplatin resistance of tumour cells. Here, we review the mechanism of action of cisplatin, the mechanism of resistance to cisplatin, the role of metabolic remodelling in tumorigenesis and development, and the effects of common metabolic pathways on cisplatin resistance.

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Glutamine addiction activates polyglutamine-based nanocarriers delivering therapeutic siRNAs to orthotopic lung tumor mediated by glutamine transporter SLC1A5

Cited by 32 publications

References 52 publications

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

The Role of Tumour Metabolism in Cisplatin Resistance

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