Anti-androgenic mechanism of a new compound

新化合物的抗雄激素机制

• 批准号: 6550419
• 负责人: CHARLES C-Y SHIH
• 金额: $ 9.98万
• 依托单位: ANDROSCIENCE CORPORATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6550419
• 关键词: androgen inhibitor; androgen receptor; antineoplastics; dehydroepiandrosterone; drug screening /evaluation; estradiol; northern blottings; pharmacokinetics; progesterone analog; prostate neoplasms; prostate specific antigen; receptor binding; receptor expression; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Androgen blockage therapy may relieve the symptom of an advanced, localized prostate tumor; however, once the tumor evolves into a hormone-refractory stage, there is no effective treatment. A continuous activation of AR by antiandrogens (used in androgen blockage therapy) or other "nonconventional" agonists may contribute to prostate cancer progression in patients after androgen deprivation. Conceptually, pharmacological agents blocking AR function evoked by not only testicular androgens but also other agonists would have a superior capacity to decrease prostate cancer incidence at both the androgen-sensitive and -insensitive stages. We recently found that a derivative of diferuloylmethane (Compound 4) inhibited dihydrotestosterone-induced androgen receptor transactivation in human prostate cancer cells. This agent also suppressed dihydrotestosterone-induced LNCaP cell growth. Furthermore, Compound 4 was effective in decreasing LNCaP cell growth and AR transactivation stimulated by hydroxyflutamide, a widely used antiandrogen. Based upon these preliminary data, we propose in this study to: (1) Further test whether Compound 4 abolishes AR function elicited by cyproterone acetate, estradiol, dehydroepiandrosterone, and androstenediol. These antiandrogen or steroid hormones have been documented to have residual AR agonist activity and may exist in significant amounts in patients after androgen blockage therapy. (2) Explore the mechanisms of action of Compound 4 to antagonize the AR. Compound 4 may disrupt the AR pathway at multiple steps. In this preliminary study, we will examine the most likely mechanisms- whether Compound 4 blocks androgen-induced biological response via a down-regulation of AR expression, or via a competitive suppression of testicular androgens' binding to the receptor. The discovery of a novel antiandrogen capable of preventing both androgen-dependent and androgen-independent prostate cancer may have a direct impact in clinical application.

描述（由申请人提供）：雄激素阻塞疗法可以缓解晚期局部前列腺肿瘤的症状；但是，一旦肿瘤演变成激素 - 抗腐败阶段，就没有有效的治疗方法。抗雄激素（用于雄激素阻滞疗法）或其他“非惯性”激动剂可能会导致雄激素剥夺后患者的前列腺癌进展。从概念上讲，不仅由睾丸雄激素和其他激动剂引起的阻塞AR功能的药理学剂将具有较高的能力，可以降低对雄激素敏感和不敏感阶段的前列腺癌发病率。我们最近发现，二甲烷（化合物4）的衍生物抑制了人类前列腺癌细胞中二氢睾丸激素诱导的雄激素受体反式激活。该药物还抑制了二氢睾丸激素诱导的LNCAP细胞生长。此外，化合物4在降低LNCAP细胞的生长和AR反式激活中被羟基氟氨酰胺刺激（一种广泛使用的抗雄激素）。基于这些初步数据，我们在这项研究中建议： （1）进一步测试化合物4是否废除乙酸氧化甲酸酯，雌二醇，脱氢表雄酮和雄激素二酚引起的AR功能。这些抗雄激素或类固醇激素已被证明具有残留的AR激动剂活性，并且在雄激素阻滞治疗后患者可能有大量存在。 （2）探索化合物4的作用机理以对抗AR。化合物4可能会在多个步骤中破坏AR路径。在这项初步研究中，我们将检查最可能的机制 - 是否通过下调AR表达或通过竞争性抑制睾丸雄激素与受体的结合来阻断雄激素诱导的生物学反应。 发现一种能够预防雄激素依赖性和雄激素独立的前列腺癌的新型抗雄激素可能在临床应用中有直接影响。