Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors
Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors
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DOI：
10.1172/jci200316116
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发表时间：
2003-01-01
影响因子：
15.9
通讯作者：
Guzmán, M
中科院分区：
文献类型：
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作者：
Casanova, ML;Blázquez, C;Guzmán, M
非黑色素瘤皮肤癌是人类最常见的恶性肿瘤之一。目前正在研究治疗这些肿瘤的不同治疗策略。鉴于大麻素对神经胶质瘤的生长抑制作用和大麻素受体的两种亚型（CB 1和CB 2）的广泛组织分布，我们研究了这些化合物在抗皮肤肿瘤治疗中的潜在效用。在这里，我们表明，CB 1和CB 2受体表达在正常皮肤和皮肤肿瘤的小鼠和人类。在细胞培养实验中，大麻素受体的药理学激活诱导致瘤表皮细胞的凋亡死亡，而非转化表皮细胞的活力保持不受影响。局部给予混合的CB 1/CB 2激动剂WIN-55，212 -2或选择性CB 2激动剂JWH-133诱导了对通过将表皮肿瘤细胞接种到裸鼠中产生的恶性肿瘤的显著生长抑制。大麻素处理的肿瘤显示凋亡细胞数量增加。这伴随着肿瘤血管形成的损害，如通过改变血管形态和降低促血管生成因子（VEGF、胎盘生长因子和血管生成素2）的表达所确定的。在大麻素治疗的肿瘤中也观察到EGF-R功能的消除。这些结果支持了一种新的治疗皮肤肿瘤的方法。
Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth-inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB1 and CB2), we studied the potential utility of these compounds in anti-skin tumor therapy. Here we show that the CB1 and the CB2 receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB1/CB2 agonist WIN-55,212-2 or the selective CB2 agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.