Oleamide derivatives suppress the spontaneous metastasis by inhibiting connexin 26.
We previously reported that overexpressing connexin 26 (Cx26) enhances the spontaneous metastasis of mouse BL6 melanoma cells. In contrast, daily intraperitoneal injections of an oleamide derivative named MI-18 potently inhibits the spontaneous metastasis of BL6 cells. In the present study, we chemically synthesized a novel oleamide derivative named MI-22 and found that it also efficiently suppressed the spontaneous metastasis of BL6 cells. Both MI-18 and MI-22 inhibited the gap junction-mediated intercellular communications (GJIC) that are formed between HeLa cells by the ectopic expression of the hCx26 and hCx32 human connexin subtypes; however, they had no effect on GJIC mediated by hCx40, hCx43 or hCx45. Fluorescently labeled MI-18 primarily localized not only at plasma membrane but also at Golgi/endosome. This suggests that this oleamide derivative may also act on the Cx26 molecules that accumulate in the Golgi/endosome because of their overexpression. Notably, neither derivative had a cytotoxic effect on HeLa cells when they were added into the tissue culture medium. Taken together, we propose that the MI-18 and MI-22 oleamide derivatives may serve as prototypes for novel and clinically important anticancer drugs.
Ohba
Yusuke
Y
Department of Synthetic Organic Chemistry, Graduate School of Pharmaceutical Science, Osaka University, Osaka, Japan.
Kanao
Yukiko
Y
Morita
Nobuyoshi
N
Fujii
Eri
E
Hohrai
Mai
M
Takatsuji
Mayuko
M
Hirose
Hideki
H
Miura
Daisaku
D
Watari
Akihiro
A
Yutsudo
Masuo
M
Zhao
Hanjun
H
Yabuta
Norikazu
N
Ito
Akihiko
A
Kita
Yasuyuki
Y
Nojima
Hiroshi
H
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000072259:Connexin 26; D017630:Connexins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control; D009829:Oleic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D009829:Oleic Acids; D000072259:Connexin 26; C029407:oleylamide