title: A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells.
abstract: We reported previously that the abnormally augmented expression of connexin 26 (Cx26) is responsible for the enhanced spontaneous metastasis of mouse BL6 melanoma cells, and that the exogenous expression of a dominant negative form of Cx26 inhibits the spontaneous metastasis of BL6. Here we show that daily intraperitoneal (i.p.) injections of oleamide, a sleep-inducing lipid hormone, weakly inhibited the spontaneous metastasis of BL6 cells. To obtain a more effective reagent, 19 oleamide derivatives were chemically synthesized and tested for their ability to inhibit the gap junction-mediated intercellular communications (GJIC) that are formed between HeLa cells by the ectopic expression of Cx26 or Cx43. One of these, denoted metastasis inhibitor-18 (MI-18), inhibited the GJIC formed by Cx26 as well as oleamide but unlike oleamide, which is a non-selective inhibitor of connexin, it did not inhibit the GJIC formed by Cx43. Daily i.p. injections of MI-18 potently blocked the spontaneous metastasis of BL6 cells down to 15% of that in the untreated control mice. MI-18 was safe because even after >7 weeks of daily injections, the survival rate of the mice was 93%. We propose that MI-18 may serve as a novel and clinically important prototype of a potent inhibitor of spontaneous metastasis.
authors.affiliation: Department of Pathology, Osaka University Medical School/Graduate School of Frontier Bioscience, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Morita
authors.forename: Daisaku
authors.initials: D
authors.lastname: Miura
authors.forename: Yu-Ichiro
authors.initials: Y
authors.lastname: Koma
authors.forename: Tatsuki R
authors.initials: TR
authors.lastname: Kataoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nojima
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000187:drug effects*; D000072259:Connexin 26; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control; D008546:Melanoma, Experimental / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D009829:Oleic Acids / Q000138:chemical synthesis / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D015996:Survival Rate; D014162:Transfection
chemical_list: D018031:Connexin 43; D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D009829:Oleic Acids; D000072259:Connexin 26; C029407:oleylamide