A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells.
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.
Ito
Akihiko
A
Department of Pathology, Osaka University Medical School/Graduate School of Frontier Bioscience, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
Morita
Nobuyoshi
N
Miura
Daisaku
D
Koma
Yu-Ichiro
Y
Kataoka
Tatsuki R
TR
Yamasaki
Hiroshi
H
Kitamura
Yukihiko
Y
Kita
Yasuyuki
Y
Nojima
Hiroshi
H
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
D018031:Connexin 43; D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D009829:Oleic Acids; D000072259:Connexin 26; C029407:oleylamide