Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Cancer Prev Res (Phila). 2011 Jan;4(1):65-75. doi: 10.1158/1940-6207.CAPR-10-0181. Epub 2010 Nov 19.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide; however, only limited therapeutic treatments are available. Hence, we investigated the role of cannabinoid receptors, CB1 and CB2, as novel therapeutic targets against NSCLC. We observed expression of CB1 (24%) and CB2 (55%) in NSCLC patients. Furthermore, we have shown that the treatment of NSCLC cell lines (A549 and SW-1573) with CB1/CB2- and CB2-specific agonists Win55,212-2 and JWH-015, respectively, significantly attenuated random as well as growth factor-directed in vitro chemotaxis and chemoinvasion in these cells. We also observed significant reduction in focal adhesion complex, which plays an important role in migration, upon treatment with both JWH-015 and Win55,212-2. In addition, pretreatment with CB1/CB2 selective antagonists, AM251 and AM630, prior to JWH-015 and Win55,212-2 treatments, attenuated the agonist-mediated inhibition of in vitro chemotaxis and chemoinvasion. In addition, both CB1 and CB2 agonists Win55,212-2 and JWH-133, respectively, significantly inhibited in vivo tumor growth and lung metastasis (∼50%). These effects were receptor mediated, as pretreatment with CB1/CB2 antagonists abrogated CB1/CB2 agonist-mediated effects on tumor growth and metastasis. Reduced proliferation and vascularization, along with increased apoptosis, were observed in tumors obtained from animals treated with JWH-133 and Win55,212-2. Upon further elucidation into the molecular mechanism, we observed that both CB1 and CB2 agonists inhibited phosphorylation of AKT, a key signaling molecule controlling cell survival, migration, and apoptosis, and reduced matrix metalloproteinase 9 expression and activity. These results suggest that CB1 and CB2 could be used as novel therapeutic targets against NSCLC.
非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因；然而，目前可用的治疗方法有限。因此，我们研究了大麻素受体 CB1 和 CB2 作为针对 NSCLC 的新型治疗靶点的作用。我们观察到 NSCLC 患者中 CB1（24%）和 CB2（55%）的表达。此外，我们已经表明，用 CB1/CB2-和 CB2 特异性激动剂 Win55,212-2 和 JWH-015 分别治疗 NSCLC 细胞系（A549 和 SW-1573），可显著减弱这些细胞中随机和生长因子导向的体外趋化性和趋化侵袭。我们还观察到，在用 JWH-015 和 Win55,212-2 处理后，黏着斑复合物（在迁移中起重要作用）的数量显著减少。此外，在用 JWH-015 和 Win55,212-2 处理之前，用 CB1/CB2 选择性拮抗剂 AM251 和 AM630 对 CB1/CB2 进行预处理，可减弱激动剂介导的体外趋化性和趋化侵袭的抑制作用。此外，CB1 和 CB2 激动剂 Win55,212-2 和 JWH-133 分别显著抑制体内肿瘤生长和肺转移（约 50%）。这些作用是受体介导的，因为用 CB1/CB2 拮抗剂预处理可消除 CB1/CB2 激动剂对肿瘤生长和转移的作用。在用 JWH-133 和 Win55,212-2 治疗的动物的肿瘤中观察到增殖和血管生成减少，凋亡增加。进一步阐明分子机制后，我们观察到 CB1 和 CB2 激动剂均抑制 AKT 的磷酸化，AKT 是控制细胞存活、迁移和凋亡的关键信号分子，并降低基质金属蛋白酶 9 的表达和活性。这些结果表明，CB1 和 CB2 可作为针对 NSCLC 的新型治疗靶点。
