epiglucan and Sarcoma

β-Glucans are well known for its various bioactivities, but the underlying mechanism has not been fully understood. This study focuses on the anti-tumor effect and the potential mechanism of a branched β-(1, 3)-glucan (LNT) extracted from Lentinus edodes. The in vivo data indicated that LNT showed a profound inhibition ratio of ~75% against S-180 tumor growth, even significantly higher than the positive control of Cytoxan (~54%). Interestingly, LNT sharply promoted immune cells accumulation into tumors accompanied by cell apoptosis and inhibition of cell proliferation during tumor development. Furthermore, LNT not only up-regulated expressions of the tumor suppressor p53, cell cycle arrestin p21 and pro-apoptotic proteins of Bax and caspase 3/9, but also down-regulated PARP1 and anti-apoptotic protein Bcl-2 expressions in tumor tissues. It was first found that LNT initiated p53-dependent signaling pathway to suppress cell proliferation in vitro, and the caspase-dependent pathway to induce cell apoptosis in vivo. The underlying anti-tumor mechanism was proposed that LNT activated immune responses to induce cell apoptosis through caspase 3-dependent signaling pathway and to inhibit cell proliferation possibly via p53-dependent signaling pathway in vivo. Besides, LNT inhibited angiogenesis by suppressing VEGF expression, leading to slow progression of tumors.

Topics: Animals; Antineoplastic Agents; Apoptosis; beta-Glucans; Caspase 3; Cell Proliferation; Cell Survival; Chemokines; Cyclophosphamide; Drug Screening Assays, Antitumor; Female; Fungal Polysaccharides; HeLa Cells; Humans; Male; Mice, Inbred BALB C; Neoplasm Transplantation; Neovascularization, Pathologic; Sarcoma; Shiitake Mushrooms; STAT3 Transcription Factor

A soluble homogeneous β-glucan, GFPBW1, with a molecular mass of 300 kDa was purified from the fraction of the fruit bodies of Grifola frondosa extracted with 5% NaOH. Using various methods, such as infrared spectroscopy, NMR, methylation and monosaccharide composition analysis, its structure was determined to be a β-D-(1-3)-linked glucan backbone with a single β-D-(1-6)-linked glucopyranosyl residue branched at C-6 on every third residue. It induced TNF-α and IL-6 production and the activation of Syk and NF-κB signaling in resident peritoneal macrophages from ICR mice, which could be significantly inhibited by the blocking reagent laminarin. A competitive phagocytosis assay with FITC-zymosan indicated that GFPBW1 could bind to DC-associated C-type lectin 1 (Dectin-1). The TNF-α secretion and activation of Syk/NF-κB signaling triggered by GFPBW1 were enhanced in RAW264.7 cells overexpressing wild but not mutant (Δ38 and Y15S) Dectin-1. Furthermore, GFPBW1 potentiated the Concanavalin A-induced proliferative response of splenocytes and inhibited Sarcoma-180 growth allografted in ICR mice but not in immunodeficient BALB/c nu/nu mice. These results suggested that the antitumor activity of GFPBW1 was partially associated with the activation of macrophages via the Dectin-1/Syk/NF-κB signaling pathway. This molecule could be a promising biological response modifier with clear application for antitumor therapies.

Topics: Animals; Antineoplastic Agents, Phytogenic; beta-Glucans; Carbohydrate Sequence; Cell Line, Tumor; Fruiting Bodies, Fungal; Gene Expression Regulation, Neoplastic; Glucans; Grifola; Injections, Subcutaneous; Interleukin-6; Intracellular Signaling Peptides and Proteins; Lectins, C-Type; Macrophages, Peritoneal; Mice; Mice, Inbred ICR; NF-kappa B; Phagocytosis; Polysaccharides; Protein-Tyrosine Kinases; Sarcoma; Signal Transduction; Syk Kinase; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays