Molecular Mechanisms of Cannabinoid Antitumor Activity

描述(申请人提供)：大麻的主要活性大麻素成分Delta9-THC已被证明是一种无毒的抗肿瘤药物，适用于多种癌症。此外，已经证明，将来自该植物的大麻素成分组合在一起的治疗方法可以比单独使用任何一种化合物提供更大的活性。这项提案将重点放在使用大麻类化合物作为选择性抗肿瘤药物治疗人脑胶质瘤的可能性上。第一个目的是研究Delta9-THC单独和与其他主要大麻素成分联合使用的抗增殖和凋亡作用。这将使用对Delta9-THC的抗肿瘤活性敏感的人类胶质瘤细胞系来完成。植物成分的活性也将与合成的大麻素配体进行比较。CBI和CBI受体是大麻素成分Delta9-THC的主要初始相互作用部位。受体蛋白的激活导致胶质瘤细胞系细胞增殖减少，细胞凋亡率增加。当与Delta9-THC联合给药时，其他天然大麻类化合物，在已知受体(CB1和CB2)上不活跃或不太活跃，与单独使用单一成分相比，可以产生增加整体药理学的效果。这种潜在的相加或协同作用将针对人类胶质瘤进行测试。对于在人脑胶质瘤中导致这些效应的细胞内信号通路，我们知之甚少。第二个目的是在人脑胶质瘤细胞系中确定大麻素抗肿瘤活性所涉及的分子途径。这将通过详细研究这些化合物的抗增殖和凋亡效应所涉及的途径来实现。利用抗体阵列技术，将扩大对先前识别的通路中受影响的信号成分的搜索，并将有可能发现新的通路。最终目的将评估最活跃的大麻素成分单一或组合对脑部肿瘤增殖的影响。总之，与Delta9-THC单独使用相比，大麻素成分的组合可能是更有效的抗人脑胶质瘤药物。这项提议将检验这一假说，并阐明导致这些效应的分子机制。

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.