Control of Breast Cancer by the Endocannabinoid System

描述(由申请人提供)：通过CB1、CB2和其他受体亚型激活内源性大麻素系统导致对多种癌症的抑制。内源性大麻素系统是通过对经典的大麻素激动剂-9-四氢大麻酚(？9-THC)和其他合成大麻素的研究发现的。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类乳腺癌的可能性上。我们已经发现，激活CB1、CB2和其他受体亚型的大麻类化合物可以抑制乳腺癌细胞的增殖和侵袭，我们还发现了下游靶点，可能将大麻受体的刺激与这些作用联系起来。此外，我们的初步研究提供了证据，内源性内源性大麻素通过激活大麻素受体抑制转移性乳腺癌细胞的增殖和侵袭。我们的初步数据还表明，大麻类化合物具有选择性疗效，对引发乳腺癌的正常人类细胞的不良影响较小。由于健康组织的毒性限制了目前癌症治疗的疗效，因此发现人体组织选择性疗效背后的机制具有临床意义。在体内，大麻素可以抑制多种类型的肿瘤生长，然而，这一点在乳腺癌中还没有确定。这项应用的第一个目的是确定选择性CB2受体激动剂是否可以像CB1/CB2受体激动剂混合使用一样有效地抑制转移性乳腺癌细胞的增殖和侵袭。与具有CB1受体活性的激动剂相比，CB2激动剂不会产生精神副作用，可能会在临床上更有用。下一步，可能涉及控制乳腺癌细胞增殖和大麻素侵袭的信号转导途径将被评估。下一个目标将是评估大麻类化合物在抑制乳腺癌细胞增殖、迁移和诱导细胞死亡方面的选择性疗效的大小。我们还将定义这些影响与下游目标变化的关系。大麻素，大麻二醇，不与CB1和CB2受体相互作用，但可以抑制乳腺癌细胞的增殖和侵袭。第三个目标是确定大麻素受体亚型的激活和特定的信号通路是否对大麻二醇的影响负责。最终目的将是确定大麻素是否可以在体内抑制乳腺癌的转移。测试申请书中概述的假设可能会导致开发出有效的乳腺癌抑制剂，或许还有其他癌症的抑制剂。这项研究还可能阐明与大麻素抗癌活性相关的新机制，并将有助于发展候选人在癌症生物学领域的职业生涯。

DESCRIPTION (provided by applicant): Activation of the endocannabinoid system through CB1, CB2 and additional receptor subtypes results in the inhibition of a broad range of cancers. The endocannabinoid system was discovered through research focusing on the classical cannabinoid agonist, ?9-tetrahydrocannabinol (?9-THC), and other synthetic cannabinoids. This proposal will focus on the potential treatment of human breast cancer using cannabinoids as selective antitumor agents. We have found that cannabinoid compounds activating CB1, CB2 and additional receptor subtypes can inhibit breast cancer cell proliferation and invasiveness and we have discovered down-stream targets that potentially link cannabinoid receptor stimulation to these effects. Furthermore, our preliminary studies provide evidence that endogenous endocannabinoid tone tonically inhibits metastatic breast cancer cell proliferation and invasiveness through the activation of cannabinoid receptors. Our preliminary data also suggests that cannabinoid compounds possess selective efficacy, having less adverse effects on the normal human cells from which the breast cancers arise. Since toxicity in healthy tissue limits the efficacy of current cancer treatments, discovering the mechanism behind selective efficacy in human tissues is of clinical importance. Cannabinoids can inhibit multiple types of tumor growth in\ vivo, however, this has not been determined for breast cancer. The first aim of this application is to determine if selective CB2 receptor agonists can inhibit metastatic breast cancer cell proliferation and invasiveness as effectively as mixed CB1/CB2 receptor agonists. CB2 agonists do not produce psychotropic side effects, as compared to agonists with CB1 receptor activity, and would potentially be more useful clinically. Next, signal transduction pathways potentially involved in control of breast cancer cell proliferation and invasion by cannabinoids will be evaluated. The next aim will be to evaluate the magnitude of selective efficacy that cannabinoids have for inhibiting breast cancer cell proliferation, migration, and inducing cell death. We will also define the relationship of these effects to alterations in downstream targets. The cannabinoid, cannabidiol, does not interact with CB1 and CB2 receptors, but can inhibit breast cancer cell proliferation and invasiveness. The third aim will be to determine if activation of a cannabinoid receptor subtype and specific signaling pathways are responsible for the effects of cannabidiol. The final aim will be to determine if cannabinoids can inhibit breast cancer metastasis in vivo. Testing the hypotheses outlined in the application may lead to the development of effective inhibitors of breast, and perhaps other, cancers. This research may also elucidate novel mechanisms related to the anticancer activity of cannabinoids, and will serve to develop the career of the candidate in the field of cancer biology.