Molecular Mechanisms of Cannabinoid Antitumor Activity

大麻素抗肿瘤活性的分子机制

• 批准号: 7048675
• 负责人: Sean D McAllister
• 金额: $ 16.29万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-05 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048675
• 关键词: antineoplastics; apoptosis; astrocytes; athymic mouse; biological signal transduction; cannabinoid receptor; cannabinoids; cell line; cell proliferation; drug discovery /isolation; drug interactions; drug screening /evaluation; glioma; microarray technology; neoplasm /cancer pharmacology; neoplastic growth; receptor expression; terminal nick end labeling; xenotransplantation

DESCRIPTION (provided by applicant): The major active cannabinoid constituent of marijuana, delta9-THC, has been shown to act as a non-toxic anti-tumor agent for a broad range of cancers. Furthermore, it has been demonstrated that treatments combining combinations of cannabinoid constituents from the plant can impart greater activity than any one compound alone. This proposal will focus on the potential treatment of human gliomas using cannabinoids as selective anti-tumor agents. The first aim is to study the anti-proliferative and apoptotic effects of delta9-THC alone and in combination with other major cannabinoid constituents. This will be accomplished using a human glioma cell line that is sensitive to the anti-tumor activity of delta9-THC. The activities of the plant constituents will also be compared to synthetic cannabinoid ligands. CBi and CBi receptors are the primary initial interaction site for the cannabinoid constituent delta9-THC. Activation of the receptor proteins leads to reduced cell proliferation and increased apoptosis in glioma cell lines. When given in combination with delta9-THC, other natural cannabinoid compounds, inactive or less active at the known receptors (CBi and CB2), can produce effects that increase the overall pharmacology compared to the use of a single constituent alone. This potential additive or synergistic effect will be tested against human gliomas. Little is known about the intracellular signaling pathways leading to these effects in human gliomas. The second Aim is to identify the molecular pathways involved in the anti-tumor activity of cannabinoids in a human glioma cell line. This will be accomplished by a detailed study of the pathways that have been implicated in the anti-proliferative and apoptotic effects of the compounds. Using antibody array technology, the search for affected signaling components within the previously identified pathways will be expanded upon and the discovery of novel pathways will also be possible. The final Aim will evaluate the effects of the most active single or combination of cannabinoid constituents on tumor proliferation in brain. In conclusion; combinations of cannabinoid constituents may be more effective anti-tumor agents towards human gliomas than delta9-THC alone. This proposal will test this hypothesis and elucidate the molecular mechanisms responsible for these effects.

描述（由申请人提供）：大麻的主要活性大麻素组成，Delta9-Thc，已被证明是多种癌症的一种无毒的抗肿瘤剂。此外，已经证明，结合植物中大麻素成分组合组合的处理可以比单独使用任何一种化合物赋予更多的活性。该建议将使用大麻素作为选择性抗肿瘤剂的潜在治疗人神经胶质瘤。第一个目的是研究单独使用Delta9-THC的抗增殖和凋亡作用，并与其他主要的大麻素组成部分结合使用。这将使用对Delta9-THC抗肿瘤活性敏感的人神经胶质瘤细胞系来完成。植物成分的活性也将与合成大麻素配体进行比较。 CBI和CBI受体是大麻素组成delta9-THC的主要初始相互作用位点。受体蛋白的激活导致细胞增殖降低和神经胶质瘤细胞系的凋亡增加。当与Delta9-THC结合使用时，与单独使用单个组成剂相比，其他天然大麻素化合物（CBI和CB2）在已知受体（CBI和CB2）中的活性（CBI和CB2）在已知受体（CBI和CB2）中的影响不足。这种潜在的添加剂或协同作用将针对人神经胶质瘤进行测试。关于导致这些在人神经胶质瘤的细胞内信号传导途径知之甚少。第二个目的是确定人神经胶质瘤细胞系中大麻素抗肿瘤活性的分子途径。这将通过对与化合物的抗增殖和凋亡作用有关的途径进行的详细研究来完成。使用抗体阵列技术，将扩展对先前识别途径中受影响的信号传导组件的搜索，并且还可以发现新的途径。最终目的将评估大麻素成分最活跃的单一或组合对大脑肿瘤增殖的影响。综上所述;与单独使用Delta9-THC相比，大麻素组成部分的组合可能是对人神经胶质瘤的有效抗肿瘤剂。该建议将检验这一假设，并阐明负责这些影响的分子机制。