Control of Breast Cancer by the Endocannabinoid System

通过内源性大麻素系统控制乳腺癌

• 批准号: 7147321
• 负责人: Sean D McAllister
• 金额: $ 14.35万
• 依托单位: CALIFORNIA PACIFIC MED CTR RES INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147321
• 关键词: breast neoplasms; cannabinoid receptor; cannabinoids; cell proliferation; endocannabinoids; human; neoplastic cell; receptor

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.

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会导致抑制广泛的癌症。内源性大麻素系统是通过重点介绍经典大麻素激动剂，“ 9-四氢大麻酚（？9-THC）和其他合成大麻素”的研究发现的。该建议将以大麻素作为选择性抗肿瘤剂的潜在治疗人类乳腺癌的治疗。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入性，并且我们发现了下游靶标，这些靶标有可能将大麻素受体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表明内源性内源性大麻素语调通过激活大麻素受体的激活来抑制转移性乳腺癌细胞的增殖和侵入性。我们的初步数据还表明，大麻素化合物具有选择性疗效，对乳腺癌的正常人细胞的不利影响较小。由于健康组织中的毒性限制了当前癌症治疗的功效，因此发现人体组织中选择性疗效的机制至关重要。大麻素可以抑制\ Vivo中多种类型的肿瘤生长，但是，这尚未确定乳腺癌。该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混合的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，并且在临床上可能更有用。接下来，将评估潜在地控制乳腺癌细胞增殖和大麻素侵袭的信号转导途径。下一个目标是评估大麻素对抑制乳腺癌细胞增殖，迁移和诱导细胞死亡的选择性疗效的大小。我们还将定义这些影响与下游目标的变化的关系。大麻素（大麻二酚）与CB1和CB2受体不相互作用，但可以抑制乳腺癌细胞的增殖和侵入性。第三个目的是确定大麻素受体亚型的激活和特定的信号通路是否负责大麻二醇的影响。最终目标是确定大麻素是否可以抑制体内乳腺癌转移。测试应用程序中概述的假设可能会导致乳腺癌和其他癌症的有效抑制剂的发展。这项研究还可以阐明与大麻素的抗癌活性有关的新型机制，并将在癌症生物学领域发展候选人的职业。