Journal Article

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

Akihiko Ito, Nobuyoshi Morita, Daisaku Miura, Yu-ichiro Koma, Tatsuki R. Kataoka, Hiroshi Yamasaki, Yukihiko Kitamura, Yasuyuki Kita and Hiroshi Nojima

in Carcinogenesis

Volume 25, issue 10, pages 2015-2022
Published in print October 2004 | ISSN: 0143-3334
Published online October 2004 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgh208
A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells

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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.

Keywords: Cx26, connexin 26; Cx43, connexin 43; GJIC, gap junction-mediated intercellular communications; MI-18, metastasis inhibitor-18; MMP, matrix metalloproteinases

Journal Article.  6368 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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