Anti-androgenic mechanism of a new compound

描述（由申请人提供）：雄激素阻断治疗可以缓解晚期局限性前列腺肿瘤的症状;然而，一旦肿瘤发展到肿瘤难治性阶段，就没有有效的治疗方法。抗雄激素（用于雄激素阻断治疗）或其他“非常规”激动剂持续激活AR可能导致雄激素剥夺后患者的前列腺癌进展。从概念上讲，阻断不仅由睾丸雄激素而且由其他激动剂诱发的AR功能的药物将具有降低雄激素敏感和不敏感阶段前列腺癌发病率的上级能力。我们最近发现，二阿魏酰甲烷（化合物4）的衍生物抑制二氢睾酮诱导的雄激素受体在人前列腺癌细胞的反式激活。该试剂还抑制二氢睾酮诱导的LNCaP细胞生长。此外，化合物4有效降低由羟基氟替卡松（一种广泛使用的抗雄激素）刺激的LNCaP细胞生长和AR反式激活。根据这些初步数据，我们在本研究中建议： （一） 进一步测试化合物4是否消除由醋酸环丙孕酮、雌二醇、脱氢表雄酮和雄烯二醇引起的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，并且可能在雄激素阻断治疗后的患者中大量存在。 （二） 探讨化合物4拮抗AR的作用机制。化合物4可以在多个步骤中破坏AR途径。在该初步研究中，我们将检查最可能的机制-化合物4是否通过AR表达的下调或通过睾丸雄激素与受体结合的竞争性抑制来阻断雄激素诱导的生物反应。 一种新型抗雄激素药物的发现，能够预防雄激素依赖性和雄激素非依赖性前列腺癌可能有直接的影响，在临床应用。

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.