title: In vitro and in vivo anticancer activity of a synthetic glycolipid as Toll-like receptor 4 (TLR4) activator.
abstract: Activation of Toll-like receptor 4 (TLR4) triggers the innate immune response and leads to the induction of adaptive immunity. TLR4 agonists are known to function as immunostimulants and exhibit promising therapeutic potential for cancer immunotherapy. We have previously developed a synthetic serine-based glycolipid (designated as CCL-34) that can activate TLR4-dependent signaling pathways. In this study, the anticancer immunity of CCL-34 was further demonstrated. CCL-34-activated macrophages induced cancer cell death via the apoptotic pathway, and this cytotoxicity was significantly inhibited by NG-monomethyl-L-arginine (an inducible NOS inhibitor). Notably, conditioned medium collected from CCL-34-treated splenocytes also induced cytotoxicity toward cancer cells. Furthermore, CCL-34 treatment suppressed tumor growth and increased the survival rate in TLR4-functional C3H/HeN mice but not in TLR4-defective C3H/HeJ mice. Increased apoptosis, the induction of cytokines (IFN-γ and IL-12) and chemokines (CXCL9 and CXCL10), and the elevation of leukocyte markers (CD11b, CD11c, CD4, and CD8) were detected at tumor sites in C3H/HeN mice but not in C3H/HeJ mice. Structure-and-activity relationship analysis of CCL-34 and its structural analogs revealed that a sugar moiety is essential for its activity. However, the substitution of the galactose in CCL-34 with glucose or fucose did not reduce its activity. Altogether, this study reveals the anticancer activity of a new synthetic TLR4 agonist and broadens the molecular basis of TLR4-activating glycolipids.
authors.affiliation: Institute of Public Health, National Yang-Ming University, Taipei 11221, Taiwan; Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan.
authors.forename: Yong-Shiang
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Li-De
authors.initials: LD
authors.lastname: Huang
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Chao-Hsiung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Po-Hsiung
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 10449, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Fen-Hwa
authors.initials: FH
authors.lastname: Wong
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: cclin66@mx.nthu.edu.tw.
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan; Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221, Taiwan. Electronic address: slfu@ym.edu.tw.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Fu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002241:Carbohydrates / Q000737:chemistry; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D016503:Drug Delivery Systems; D006017:Glycolipids / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012694:Serine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C570114:CCL 34; D002241:Carbohydrates; D006017:Glycolipids; D051197:Toll-Like Receptor 4; D012694:Serine; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3