Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.
Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.
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DOI：
10.1158/1535-7163.mct-09-0448
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发表时间：
2009-11
影响因子：
5.7
通讯作者：
Ganju RK
中科院分区：
文献类型：
--
作者：
Qamri Z;Preet A;Nasser MW;Bass CE;Leone G;Barsky SH;Ganju RK
据报道，大麻素具有抗肿瘤活性。然而，关于合成的非精神病性大麻素对乳腺癌生长和转移的作用和作用机制，人们知之甚少。我们已经表明，大麻素受体CB1和CB2在原发性人类乳腺肿瘤中过表达，与正常乳腺组织相比。我们还观察到乳腺癌细胞系MDA-MB 231、MDA-MB 231-luc和MDA-MB 468表达CB 1和CB 2受体。此外，我们已经表明，CB2合成激动剂JWH-133和CB1和CB2激动剂WIN-55，212 - 2在体外条件下抑制细胞增殖和迁移。这些结果在各种小鼠模型系统中得到体内证实。用JWH-133或WIN-55，212 - 2治疗的小鼠显示肿瘤生长减少40%至50%，肺转移减少65%至80%。CB1和CB2拮抗剂AM 251和SR 144528分别逆转这些作用，表明CB1和CB2受体参与。此外，CB2激动剂JWH-133在多瘤中T癌蛋白（PyMT）转基因小鼠模型系统中显示出延迟和减少乳腺肿瘤。在进一步阐明后，我们观察到JWH-133和WIN-55，212 - 2通过协调调节环氧合酶-2/前列腺素E2信号通路和诱导细胞凋亡来介导乳腺肿瘤抑制作用。这些结果表明，CB1和CB2受体可用于开发新的治疗策略，对乳腺癌的生长和转移。
Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/ prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.