A new strategy to block tumor growth by inhibiting endocannabinoid inactivation

被引:132
作者
Bifulco, M
Laezza, C
Valenti, M
Ligresti, A
Portella, G
Di Marzo, V
机构
[1] CNR, Ist Chim Biomol, I-80078 Pozzuoli, NA, Italy
[2] Univ Naples Federico II, Dipartimento Biol & Patol Cellulare & Mol L Calif, Naples, Italy
[3] Univ Naples Federico II, CNR, Endocannabinoid Res Grp, Naples, Italy
[4] Univ Naples Federico II, CNR, Ist Endocrinol & Oncol Sperimentale, Naples, Italy
[5] Univ Salerno, Dipartimento Sci Farmaceut, I-84084 Fisciano, SA, Italy
关键词
AA-5-HT; VDM-11; KiMol;
D O I
10.1096/fj.04-1754fje
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Endocannabinoid signaling has been shown to be enhanced in several cancer tissues and malignant cells, and studies in cell lines have shown that this up-regulation might serve the purpose of providing transformed cells with a further means to inhibit their proliferation. Here we investigated the effect of inhibitors of endocannabinoid degradation on the growth of rat thyroid tumor xenografts induced in athymic mice. VDM-11, a selective inhibitor of endocannabinoid cellular re-uptake, and arachidonoyl- serotonin (AA-5-HT), a selective blocker of endocannabinoid enzymatic hydrolysis, both inhibited the growth in vivo of tumor xenografts induced by the subcutaneous injection of rat thyroid transformed (KiMol) cells. This effect was accompanied by significantly enhanced endocannabinoid concentrations in the tumors excised at the end of the in vivo experiments. Endocannabinoids, as well as VDM-11 and AA-5-HT, inhibited the growth in vitro of the transformed rat thyroid cells used to induce the tumors in vivo, and their effect was reversed at least in part by the cannabinoid CB1 receptor antagonist SR141716A. This compound, however, when administered alone, did not enhance, but instead slightly inhibited, the growth of rat thyroid transformed cells both in vitro and in tumor xenografts induced in vivo. These findings indicate that endocannabinoids tonically control tumor growth in vivo by both CB1-mediated and non-CB1-mediated mechanisms and that, irrespective of the molecular mechanism of their anti-proliferative action, inhibitors of their inactivation might be used for the development of novel anti-cancer drugs.
引用
收藏
页码:1606 / +
页数:14
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