RRC ID 69471
Author Sasaki K, Nishina S, Yamauchi A, Fukuda K, Hara Y, Yamamura M, Egashira K, Hino K.
Title Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice.
Journal Cell Mol Gastroenterol Hepatol
Abstract 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.
Volume 11(3)
Pages 739-762
Published 2021-1-1
DOI 10.1016/j.jcmgh.2020.10.010
PII S2352-345X(20)30173-9
PMID 33191170
PMC PMC7841526
MeSH Animals Antineoplastic Combined Chemotherapy Protocols / administration & dosage* CD8-Positive T-Lymphocytes / immunology CD8-Positive T-Lymphocytes / metabolism Carcinoma, Hepatocellular / chemically induced Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / immunology Carcinoma, Hepatocellular / pathology Cell Culture Techniques Cell Line, Tumor Coculture Techniques Deoxyglucose / administration & dosage* Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / immunology Drug Synergism Humans Immune Checkpoint Inhibitors / administration & dosage Interferon-gamma / metabolism Liver Neoplasms / drug therapy* Liver Neoplasms / immunology Liver Neoplasms / pathology Liver Neoplasms, Experimental / chemically induced Liver Neoplasms, Experimental / drug therapy* Liver Neoplasms, Experimental / immunology Liver Neoplasms, Experimental / pathology Male Mice Nanoparticle Drug Delivery System / chemistry Polylactic Acid-Polyglycolic Acid Copolymer / chemistry Tumor Escape / drug effects Warburg Effect, Oncologic / drug effects Xenograft Model Antitumor Assays
Human and Animal Cells OS-RC-2(RCB0735)