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Carcinogenesis Advance Access originally published online on June 17, 2004
Carcinogenesis 2004 25(10):2015-2022; doi:10.1093/carcin/bgh208
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Carcinogenesis vol.25 no.10 © Oxford University Press 2004; all rights reserved.

ARTICLE

A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells

Akihiko Ito1,*, Nobuyoshi Morita2,*, Daisaku Miura4, Yu-ichiro Koma1, Tatsuki R. Kataoka1, Hiroshi Yamasaki5, Yukihiko Kitamura1, Yasuyuki Kita2 and Hiroshi Nojima3,6

1 Department of Pathology, Osaka University Medical School/Graduate School of Frontier Bioscience, 2 Department of Synthetic Organic Chemistry, Graduate School of Pharmaceutical Science, 3 Department of Molecular Genetics, Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan, 4 Biosafety Research Center for Foods, Drugs and Pesticides, Iwata-gun, Shizuoka 437-1213, Japan and 5 School of Science and Technology, Kansei Gakuin University, Sanda, Hyogo 669-1337, Japan

6 To whom correspondence should be addressed Email: snj-0212{at}biken.osaka-u.ac.jp

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.


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