title: Resveratrol sensitized leukemia stem cell-like KG-1a cells to cytokine-induced killer cells-mediated cytolysis through NKG2D ligands and TRAIL receptors.
abstract: Human promyeloblastic leukemia KG-1a cells exhibit many characteristics similar to leukemia stem cells, which are resistant to chemotherapeutic drugs and hyposensitive to cytotoxic cells. Resveratrol (RES), as a member of plant polyphenols, has gained considerable attention due to its ability to prevent cancer from progressing. In this study, the potential of RES to sensitize KG-1a cells to cytolysis of cytokine-induced killer cells (CIKs) through NKG2D ligands and TNF-related apoptosis-inducing ligand (TRAIL) receptors were investigated. Twenty-five micromolars RES was found to inhibit approximately 50% of KG-1a cell growth and had the least growth-inhibition effect on peripheral blood mononuclear cells (PBMCs) after 24 h. Utilizing cytokines including interleukin-2 (IL-2) and interleukin-15 (IL-15) to activate PBMCs, we obtained substantial CD3 (+) CD56 (+) natural killer cell-like T lymphocytes that secreted cytokine interferon-γ (IFN-γ) and expressed NKG2D and TRAIL on their surfaces (i.e., cytokine-induced killer cells, CIKs). RES was shown to render KG-1a cells susceptible to CIK-mediated cytolysis estimated by LDH-release assay. This heightened sensitivity correlated with an increase in cell-surface expression of NKG2D ligands and death receptor 4 (DR4), coupled with a downregulation of cell-surface expression of decoy receptor 1 (DcR1) in KG-1a cells. Blocking NKG2D ligands or TRAIL with monoclonal antibodies could abrogate CIKs-mediated cytolysis. These results demonstrated that increased sensitivity of KG-1a cells, modulated by RES to alloreactive CIKs-mediated cytolysis is a phenomenon attributable to induced expression of NKG2D ligands and activation of TRAIL pathway. Thus, resveratrol combined with alloreactive CIKs merits clinical evaluation as a novel and effective immunotherapy strategy to eliminate residual leukemia stem cells.
authors.affiliation: Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Liangshan
authors.initials: L
authors.lastname: Hu
authors.forename: Donglin
authors.initials: D
authors.lastname: Cao
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Li
authors.forename: Yanjie
authors.initials: Y
authors.lastname: He
authors.forename: Kunyuan
authors.initials: K
authors.lastname: Guo
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D055612:Cytokine-Induced Killer Cells / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D013267:Stilbenes; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human; D000077185:Resveratrol