Prostate Cancer Chemoprevention using a Natural Agent

描述（由申请人提供）：前列腺癌（PCa）的长潜伏期为化学预防策略提供了机会之窗。大多数此类策略集中于控制和/或逆转肿瘤转化和癌症进展的机制。人们普遍认为，在发展和进展过程中，肿瘤细胞会逃避患者的防御系统。在这方面，自然杀伤（NK）细胞是先天免疫系统的细胞效应物，是激活宿主防御系统和破坏肿瘤细胞所必需的。然而，在PCa患者中，NK细胞的功能及其数量经常受损和/或耗尽。因此，通过免疫调节化合物增强NK细胞的功能是预防前列腺癌的一种很有前途的方法。最近，我们证明了从穿心莲（穿心莲）中分离的天然化合物穿心莲内酯（AG）对NK细胞的免疫调节作用，并在患有PCa PTEN同基因肿瘤的小鼠中建立了其抗肿瘤作用。我们的初步结果为研究AG在增强NK细胞中的作用提供了理论依据，NK细胞可以消除PCa细胞。基于这些令人鼓舞的初步数据，我们假设AG通过增强NK细胞的抗肿瘤活性来抑制PCa的生长，从而为PCa提供了一种创新的、基于免疫的化学预防策略。为了验证这一假设，我们提出了两个具体目标。第一个目标将使用小鼠模型来确定AG在促进NK细胞活性对抗PCa方面的潜力。这将通过建立AG通过NK细胞动员和细胞毒性活性的体内效应与AG通过NK细胞调节细胞因子产生的适应性T细胞反应的有效性之间的相互关系来实现。在第二个目标中，我们将建立AG对NK细胞发育、增殖/存活和细胞毒性功能的影响。这些研究将确定AG通过增强NK细胞功能实现PCa化学预防的有效性，使该建议具有临床相关性和高度可翻译性。

DESCRIPTION (provided by applicant): The long latency of prostate cancer (PCa) provides a window of opportunity for chemoprevention strategies. Most such strategies are focused on controling and/or reversing the mechanisms involved in neoplastic transformation and cancer progression. It is well accepted that, during development and progression, tumor cells evade the patient's defense system. In this regard, natural killer (NK) cells are cellular effectors of the innate immune system and are required for activation of the host defense system and for destruction of tumor cells. In PCa patients, however, the function of NK cells and their numbers are often compromised and/or depleted. Therefore, enhancing the function of NK cells by immunomodulatory compounds is a promising approach for PCa prevention. Recently, we demonstrated the immunomodulatory effects of andrographolide (AG), a natural compound isolated from Andrographis paniculata (AP), on NK cells and have established its antitumor effects in mice bearing PCa PTEN syngeneic tumors. Our preliminary results provide a rationale to investigate the function of AG in potentiating NK cells, which can act to eliminate PCa cells. Based on these encouraging preliminary data, we hypothesize that AG inhibits PCa growth by potentiating the anti-tumor activity of NK cells, thus offering an innovative, immune-based chemopreventive strategy for PCa. To test this hypothesis, we propose two specific aims. The first aim will use mouse models to determine the potential of AG in boosting NK cell activity against PCa. This will be achieved by establishing an interrelationship between the in vivo effects of AG through NK cel mobilization and cytotoxic activities and the effectiveness of AG in adaptive T cell responses through modulation of cytokine production by NK cells. In the second aim, we will establish the effects of AG on development, proliferation/survival, and cytotoxic function of NK cells. These studies, which will determine the effectiveness of AG in PCa chemoprevention achieved through boosting NK cell function, make the proposal clinically relevant and highly translational.