title: Tumor specific cytotoxicity of beta-glucosylceramide: structure-cytotoxicity relationship and anti-tumor activity in vivo.
abstract: This study describes the structure-cytotoxicity relationship of beta-glucosylceramide (beta-GluCer) and its antitumor activity in vivo. Unglycosylated ceramide had no selective cytotoxicity which demonstrated that the sugar moiety plays a critical role for the expression of selective cytotoxicity by beta-GluCer. beta-Galactosylceramide also showed tumor specific cytotoxicity suggesting that the chemical structure of sugar group is not a factor for the selective toxicity. Similarly, unglycosylated ceramides of short acyl chain also selectively inhibited the growth of cancer cells. These findings in concert point to the importance of the hydrophilicity of the ceramide molecule rather than the chemical structure for the cyto-selectivity. Treatment of the cells with beta-GluCer increased the concentration of reactive oxygen species leading to cell cycle arrest and necrosis. Intraperitoneal administration of beta-GluCer significantly suppressed the growth of tumor implanted to the back of mice. beta-GluCer also induced antitumor immunity via the activation of NKT cells in vivo, and decreased the tumor metastasis of lymphoma cells. The present study thus demonstrated the antitumor activity of beta-GluCer in vivo, and discussed the mechanisms responsible for the growth inhibition.
authors.affiliation: Center of Molecular Biosciences, University of the Ryukyus, Nishihara, Okinawa, Japan. okuhiros@comb.u-ryukyu.ac.jp
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Oku
authors.forename: Changchun
authors.initials: C
authors.lastname: Li
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimatani
authors.forename: Hironori
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Toda
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okabe
authors.forename: Hisami
authors.initials: H
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005963:Glucosylceramides / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007274:Injections, Intraperitoneal; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000473:pathology; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005963:Glucosylceramides; D017382:Reactive Oxygen Species