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，可抑制多种癌症。内源性大麻素系统是通过对经典大麻素激动剂的研究发现的。9-tetrahydrocannabinol (?9-THC)和其他合成大麻素。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乳腺癌的潜在方法。我们发现，激活CB1、CB2和其他受体亚型的大麻素化合物可以抑制乳腺癌细胞的增殖和侵袭性，我们还发现了可能将大麻素受体刺激与这些作用联系起来的下游靶点。此外，我们的初步研究提供了内源性内源性大麻素通过激活大麻素受体来抑制转移性乳腺癌细胞增殖和侵袭性的证据。我们的初步数据还表明，大麻素化合物具有选择性功效，对乳腺癌产生的正常人类细胞的不良影响较小。由于健康组织中的毒性限制了当前癌症治疗的疗效，因此发现人体组织中选择性疗效背后的机制具有临床重要性。大麻素可以抑制多种类型的肿瘤在体内的生长，然而，这还没有确定对乳腺癌。本应用的第一个目的是确定选择性CB2受体激动剂是否能像混合CB1/CB2受体激动剂一样有效地抑制转移性乳腺癌细胞的增殖和侵袭性。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，可能在临床上更有用。接下来，大麻素可能参与控制乳腺癌细胞增殖和侵袭的信号转导途径将被评估。下一个目标将是评估大麻素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功效的大小。我们还将定义这些效应与下游靶标变化的关系。大麻素（cannabidiol）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性。第三个目标是确定大麻素受体亚型和特定信号通路的激活是否与大麻二酚的作用有关。最终目的将是确定大麻素是否可以抑制乳腺癌在体内的转移。测试应用程序中概述的假设可能会导致开发有效的乳腺癌抑制剂，也许还有其他癌症。该研究还可能阐明大麻素抗癌活性的新机制，并将有助于候选人在癌症生物学领域的发展。

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.