Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms
Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms
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DOI：
10.1111/j.1476-5381.2012.02027.x
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Di Marzo, Vincenzo
中科院分区：
文献类型：
--
作者：
De Petrocellis, Luciano;Ligresti, Alessia;Di Marzo, Vincenzo
背景和目的大麻素受体激活可诱导前列腺癌细胞凋亡，但大麻素以外的其他物质？9-对大麻素受体缺乏效力的四氢大麻酚（THC）尚未被研究。这些化合物中的一些拮抗瞬时受体电位melastatin 8型（TRPM 8）通道，其表达是雄激素受体（AR）依赖性PCC存活所必需的。实验方法我们测试了纯大麻素和来自富含特定大麻素（BDS）的大麻菌株的提取物，在AR阳性的（LNCaP和22 RV 1）和-阴性（DU-145和PC-3）细胞，通过评价细胞活力（MTT试验）、细胞周期停滞和凋亡诱导，通过FACS扫描、半胱天冬酶3/7测定、DNA片段化和TUNEL，和由LNCaP和DU-145细胞诱导的异种移植肿瘤的大小。大麻二酚（CBD）显著抑制细胞活力。其他化合物在去除血清24小时的细胞中变得有效。在血清存在下，几种BDS比纯化合物更有效。CBD-BDS（i.p.）增强了比卡鲁胺和多西他赛对LNCaP和DU-145异种移植肿瘤的作用，并且单独给药时，减小了LNCaP异种移植物的大小。CBD（110 μ M）诱导细胞凋亡并诱导内在细胞凋亡途径的标记物（CD 4A和CHOP表达和细胞内Ca 2+）。在LNCaP细胞中，CBD的促凋亡作用仅部分是由于TRPM 8拮抗作用，并伴随着AR、p53激活和活性氧升高的下调。分化为雄激素不敏感的神经内分泌样细胞的LNCaP细胞对CBD诱导的凋亡更敏感。这些数据支持CBD对前列腺癌的临床试验。链接文章本文由Pacher等人评论，pp.第7678章这个问题要查看此评论，请访问http://dx.doi.org/10.1111/j.1476-5381.2012.02121.x
BACKGROUND AND PURPOSE Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than ?9-tetrahydrocannabinol (THC), which lack potency at cannabinoid receptors, have not been investigated. Some of these compounds antagonize transient receptor potential melastatin type-8 (TRPM8) channels, the expression of which is necessary for androgen receptor (AR)-dependent PCC survival. EXPERIMENTAL APPROACH We tested pure cannabinoids and extracts from Cannabis strains enriched in particular cannabinoids (BDS), on AR-positive (LNCaP and 22RV1) and -negative (DU-145 and PC-3) cells, by evaluating cell viability (MTT test), cell cycle arrest and apoptosis induction, by FACS scans, caspase 3/7 assays, DNA fragmentation and TUNEL, and size of xenograft tumours induced by LNCaP and DU-145 cells. KEY RESULTS Cannabidiol (CBD) significantly inhibited cell viability. Other compounds became effective in cells deprived of serum for 24 h. Several BDS were more potent than the pure compounds in the presence of serum. CBD-BDS (i.p.) potentiated the effects of bicalutamide and docetaxel against LNCaP and DU-145 xenograft tumours and, given alone, reduced LNCaP xenograft size. CBD (110 mu M) induced apoptosis and induced markers of intrinsic apoptotic pathways (PUMA and CHOP expression and intracellular Ca2+). In LNCaP cells, the pro-apoptotic effect of CBD was only partly due to TRPM8 antagonism and was accompanied by down-regulation of AR, p53 activation and elevation of reactive oxygen species. LNCaP cells differentiated to androgen-insensitive neuroendocrine-like cells were more sensitive to CBD-induced apoptosis. CONCLUSIONS AND IMPLICATIONS These data support the clinical testing of CBD against prostate carcinoma. LINKED ARTICLE This article is commented on by Pacher et al., pp. 7678 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02121.x