Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice

Yamauchi, Akira ; Yamamura, Masahiro ; et al.

In: Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Jg. 11 (2021), Heft 3, S. 739-762

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Background & Aims Immune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg effect recently has gained attention as a cancer immune-resistance mechanism. Considering glycolysis inhibitors as therapeutic agents, their specific delivery to cancer cells is critical not to induce adverse effects. Thus, we investigated antitumor effects of a glycolysis inhibitor, consisting of 2-deoxy-D-glucose (2DG)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-NPs), against hepatocellular carcinoma in mice. Methods The antitumor effects of 2DG-PLGA-NPs were examined using hepatoma cell lines, xenograft tumors, and hepatocarcinogenic and syngeneic mouse models. Results The 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T-cell trafficking. In addition, 2DG-PLGA-NPs induced decreased lactate production and increased interferon-γ–positive T cells in liver tumors. Human CD8+ T cells cocultured with 2DG-PLGA-NP–treated Huh7 cells showed their increased interferon-γ production and glucose uptake compared with the CD8+ T cells co-cultured with PLGA-NP–treated Huh7 cells. Chemotaxis of CD8+ T cells was suppressed by lactate and enhanced by glucose. Interferon-γ enhanced CD8+ T-cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9/CXCL10) production in liver tumors via interferon-γ–Janus kinase–signal transducers and activator of transcription pathway and 5' adenosine monophosphate-activated protein kinase–mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by sorafenib or an anti–programmed death-1 antibody, but also suppressed anti–programmed death-1–resistant tumors. Conclusions The newly developed 2DG-PLGA-NPs showed antitumor immunity and cytotoxicity in liver tumors in mice, suggesting the potential of 2DG-PLGA-NPs for future clinical applications.

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Titel:	Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice
Autor/in / Beteiligte Person:	Yamauchi, Akira ; Yamamura, Masahiro ; Hino, Keisuke ; Sasaki, Kyo ; Hara, Yuichi ; Kotaro, Fukuda ; Nishina, Sohji ; Egashira, Kensuke
Link:	View record in OpenAIRE (Volltext) https://doi.org/10.1016/j.jcmgh.2020.10.010
Zeitschrift:	Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Jg. 11 (2021), Heft 3, S. 739-762
Veröffentlichung:	Elsevier BV, 2021
Medientyp:	unknown
ISSN:	2352-345X (print)
DOI:	10.1016/j.jcmgh.2020.10.010
Schlagwort:	Male 0301 basic medicine Chemokine Glucose uptake Cell Culture Techniques PLGA, poly(lactic-co-glycolic acid) 2-NDBG, 2-(N-[nitrobenz-2-oxa1,3-diazol-4-yl]amino)-2-deoxyglucose CD8-Positive T-Lymphocytes TNF-α, tumor necrosis factor-α 2DG, 2-Deoxy-D-glucose Mice chemistry.chemical_compound Liver Neoplasms, Experimental 0302 clinical medicine Polylactic Acid-Polyglycolic Acid Copolymer Antineoplastic Combined Chemotherapy Protocols Warburg Effect, Oncologic GSH, glutathione Cytotoxic T cell IFN-γ, interferon-γ Cytotoxicity Immune Checkpoint Inhibitors IFN-γ Original Research biology Chemistry Programmed Death 1 Liver Neoplasms EZH2, enhancer of zeste homologue 2 Gastroenterology PLGA Drug Synergism CCL, C-C motif chemokine mRNA, messenger RNA 030211 gastroenterology & hepatology FITC, fluorescein isothiocyanate JAK, Janus kinase Carcinoma, Hepatocellular ATP, adenosine triphosphate CCR, C-C chemokine receptor type 4 ICG, indocyanine green Treg, regulatory T cell mTOR, mammalian target of rapamycin macromolecular substances Deoxyglucose H3K27me3, H3 lysine 27 trimethylation STAM, stelic animal model STAT, signal transducers and activator of transcription ER, endoplasmic reticulum Interferon-gamma homologue, 2 03 medical and health sciences ROS, reactive oxygen species FBS, fetal bovine serum Cell Line, Tumor Animals Humans CXCL10 lcsh:RC799-869 PD1, programmed death 1 18F-FDG, 18F-2-fluoro-2-deoxyglucose Hepatology technology, industry, and agriculture Xenograft Model Antitumor Assays Coculture Techniques AMPK, AMP-activated protein kinase PD-L1, programmed death-ligand 1 030104 developmental biology Drug Resistance, Neoplasm Cancer cell Cancer research biology.protein Lactate lcsh:Diseases of the digestive system. Gastroenterology Tumor Escape NP, nanoparticles Nanoparticle Drug Delivery System HCC, hepatocellular carcinoma 2-Deoxy-D-glucose CD8 DAPI, 4′,6-diamidino-2-phenylindole DEN, diethylnitrosamine
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