Molecular Mechanisms of Cannabinoid Antitumor Activity

描述（由申请人提供）：大麻的主要活性大麻素成分，delta 9-THC，已被证明是一种无毒的抗肿瘤剂，用于广泛的癌症。此外，已经证明，组合来自植物的大麻素成分的组合的处理可以赋予比单独的任何一种化合物更大的活性。该提案将重点关注使用大麻素作为选择性抗肿瘤药物治疗人类神经胶质瘤的可能性。第一个目的是研究delta 9-THC单独和与其他主要大麻素成分组合的抗增殖和凋亡作用。这将使用对delta 9-THC的抗肿瘤活性敏感的人神经胶质瘤细胞系来实现。植物成分的活性也将与合成大麻素配体进行比较。CBi和CBi受体是大麻素成分δ 9-THC的主要初始相互作用位点。受体蛋白的激活导致胶质瘤细胞系中细胞增殖减少和细胞凋亡增加。当与δ 9-THC组合给予时，与单独使用单一成分相比，对已知受体（CB 1和CB 2）无活性或活性较低的其他天然大麻素化合物可产生增加总体药理学的效果。将针对人神经胶质瘤测试这种潜在的加和或协同效应。在人类神经胶质瘤中导致这些效应的细胞内信号通路知之甚少。第二个目的是确定大麻素在人脑胶质瘤细胞系中的抗肿瘤活性所涉及的分子途径。这将通过详细研究化合物的抗增殖和凋亡作用中涉及的途径来实现。使用抗体阵列技术，在以前确定的途径中寻找受影响的信号传导组分将得到扩展，并且新途径的发现也将成为可能。最终目的将评估大麻素成分中最具活性的单一或组合对脑中肿瘤增殖的影响。总之，大麻素成分的组合可能是比单独的δ 9-THC更有效的抗肿瘤剂。这项提议将检验这一假设，并阐明这些影响的分子机制。

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.