A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells
A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells
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DOI：
10.1093/carcin/bgh208
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发表时间：
2004-10-01
期刊：
影响因子：
4.7
通讯作者：
Nojima, H
中科院分区：
文献类型：
--
作者：
Ito, A;Morita, N;Nojima, H
我们以前报道，连接蛋白26（Cx 26）的异常增加的表达是负责增强自发转移的小鼠BL 6黑色素瘤细胞，和Cx 26的显性阴性形式的外源性表达抑制自发转移的BL 6。在这里，我们显示每日腹膜内（i. p.）注射油酸酰胺，一种睡眠诱导脂质激素，微弱地抑制了BL 6细胞的自发转移。为了获得更有效的试剂，化学合成了19种油酰胺衍生物，并测试了它们抑制由Cx 26或Cx43的异位表达在HeLa细胞之间形成的差距连接介导的细胞间通讯（GJIC）的能力。其中之一，称为转移抑制剂-18（MI-18），抑制由Cx 26以及油酰胺形成的GJIC，但与油酰胺不同，油酰胺是连接蛋白的非选择性抑制剂，它不抑制由Cx43形成的GJIC。每天腹膜内注射MI-18有效地阻断BL 6细胞的自发转移，其阻断率降至未处理对照小鼠的15%。MI-18是安全的，因为即使在>7周的每日注射后，小鼠的存活率仍为93%。我们建议MI-18可以作为一种新的和临床上重要的原型的一种有效的抑制自发转移。
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.