title: The combination therapy of α-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice.
abstract: α-Galactosylceramide (α-GalCer) has been reported to be therapeutic against metastatic liver tumors in mice. However, little is known regarding the efficacy of combined chemo-immunotherapy using α-GalCer and anticancer drugs. In this study, we evaluated the antitumor effect of the combination therapy of α-GalCer and 5-fluorouracil (5-FU) against liver tumors of MC38 colon cancer cells. The liver weights of tumor-bearing mice treated with the combination were significantly lower than those of nontreated mice and of mice treated with 5-FU or α-GalCer alone. No toxic effects on the liver and renal functions were observed in any of the treatment groups. α-GalCer treatment induced significant activation of liver NK cells in vivo, but 5-FU treatment did not. 5-FU treatment resulted in a significant upregulation of NKG2D activating molecules (Rae-1 and H60) and DNAM-1 ligands (CD112 and CD155) on MC38 cells, but α-GalCer did not. The cytolytic activity of α-GalCer-activated liver mononuclear cells against 5-FU-treated MC38 cells was significantly higher than that against nontreated cells. The increase of the cytolytic activity induced by 5-FU partially depended on NKG2D-Rae-1 or H60 signals. Depletion of NK cells significantly inhibited the antitumor efficacy of 5-FU against MC38 liver tumors, which suggested that the antitumor effect of 5-FU partially depended on the cytolytic activity of NK cells. These results demonstrated that the combination therapy of α-GalCer and 5-FU produced synergistic antitumor effects against liver tumors by increasing the expression of NK activating molecules on cancer cells. This study suggests a promising new chemo-immunotherapy against metastatic liver cancer.
authors: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Hiroshi
authors: H
authors: Aketa
authors: Tomohide
authors: T
authors: Tatsumi
authors: Keisuke
authors: K
authors: Kohga
authors: Hinako
authors: H
authors: Tsunematsu
authors: Satoshi
authors: S
authors: Aono
authors: Satoshi
authors: S
authors: Shimizu
authors: Takahiro
authors: T
authors: Kodama
authors: Takatoshi
authors: T
authors: Nawa
authors: Minoru
authors: M
authors: Shigekawa
authors: Hayato
authors: H
authors: Hikita
authors: Ryotaro
authors: R
authors: Sakamori
authors: Atsushi
authors: A
authors: Hosui
authors: Takuya
authors: T
authors: Miyagi
authors: Naoki
authors: N
authors: Hiramatsu
authors: Tatsuya
authors: T
authors: Kanto
authors: Norio
authors: N
authors: Hayashi
authors: Tetsuo
authors: T
authors: Takehara
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D005699:Galactosylceramides / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D005472:Fluorouracil
keywords: 5-FU; NK cells; liver tumor; α-GalCer