Carcinogenesis Advance Access published online on June 17, 2004
Carcinogenesis, doi:10.1093/carcin/bgh208
© 2004 by Oxford University Press
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1 Department of Pathology, Osaka University Medical School/Graduate School of Frontier Bioscience, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
* To whom correspondence should be addressed. E-mail: hnjm2606{at}biken.osaka-u.ac.jp.
We previously reported 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 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 MI-18, inhibited the GJIC formed by Cx26 as well as oleamide but unlike oleamide, which is a nonselective inhibitor of connexin, it did not inhibit the GJIC formed by Cx43. Daily intraperitoneal 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 more than seven 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.
Revised May 28, 2004
Accepted May 31, 2004
CARCINOGENESIS
A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells
2 Department of Synthetic Organic Chemistry, Graduate School of Pharmaceutical Science, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
3 Biosafety Research Center for Foods, Drugs and Pesticides, Iwata-gun, Shizuoka 437-1213, Japan
4 School of Science and Technology, Kansei Gakuin University, Sanda, Hyogo 669-1337, Japan
5 Department of Molecular Genetics, Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan
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