Augmentation of NK cell-mediated anti-cancer activity by dietary BITC

通过膳食 BITC 增强 NK 细胞介导的抗癌活性

• 批准号: 7701342
• 负责人: Per H. Basse
• 金额: $ 16.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7701342
• 关键词: Animals; Cancerous; Cell physiology; Cells; Cellular biology; Clinical; Clinical Trials; Development; Dietary Component; Dietary intake; Disease model; Drug or chemical Tissue Distribution; Epidemiologic Studies; Genetic; Goals; Human; Immunity; In Vitro; Intake; Interferon Type II; Kinetics; Lytic; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Mus; Natural Killer Cells; Neoplasm Metastasis; Outcome Study; Phenotype; Primary Neoplasm; Production; Research Design; Risk; Role; Testing; Tumor Necrosis Factor-alpha; Virus; base; benzyl isothiocyanate; cancer chemoprevention; cancer prevention; carcinogenesis; cruciferous vegetable; experience; in vitro activity; in vivo; insight; killings; neoplastic cell; novel; pre-clinical; prostate cancer prevention; prostate carcinogenesis; public health relevance; stem; tumor

DESCRIPTION (provided by applicant): Natural killer (NK) cells are able to recognize and kill aberrant (i.e., cancerous and virus-infected) cells without priming and independently of the antigenic presentation/composition of the target. NK cells have been shown to protect against development of cancer. Accordingly, identification and pre-clinical/clinical development of agents that are relatively safe but can boost NK cell function are highly desirable with immense translational application for chemoprevention of cancers. This project seeks to test a novel hypothesis that prostate cancer prevention by benzyl isothiocyanate (BITC), a constituent of many edible cruciferous vegetables, is at least in part mediated by augmentation of NK cell function. This hypothesis stems from our novel preliminary unpublished results showing BITC-mediated augmentation of NK cell lytic activity in vitro at pharmacologically relevant concentrations. In addition, the BITC-mediated augmentation of NK cell lytic activity correlates with increased production of interferon gamma (IFN3) and tumor necrosis factor-alpha (TNF1) by the NK cells. Despite these encouraging results, the in vivo significance of these in vitro observations is unclear. Likewise, the mechanism by which BITC augments NK cell activity remains elusive. The overall objective of this application is to systematically probe into these questions using prostate cancer as a disease model. The rationale for focusing on prostate cancer is based on the following considerations: (a) epidemiological studies have indicated an inverse correlation between dietary intake of cruciferous vegetables and the risk of prostate cancer, and (b) a very recent study has provided important genetic evidence for surveillance of primary tumors by NK cells in the TRAMP model of prostate cancer. The specific aims of this proposal are to (1) determine the concentration effect relationship for dietary BITC administration on tumoricidal activity of NK cells in vivo and to gain insight into the mechanism of this effect, and (2) determine whether dietary BITC- mediated boost of NK cell activity leads to suppression of prostate carcinogenesis and metastasis in TRAMP mice in vivo. Positive outcome of these studies will form a firm basis for clinical trials to determine BITC-mediated augmentation of NK cell activity and prostate carcinogenesis in humans. ) PUBLIC HEALTH RELEVANCE: We have found that dietary benzyl-isothiocyanate (BITC) is able to augment host NK cell function. In this project, we will investigate the in vivo aspects of BITC intake on the tumoricidal capacity of the host's NK cells. We will first determine the concentration effect relationship for dietary BITC administration on the tumoricidal activity of NK cells in vivo and we will determine the mechanism behind this effect. We will then determine whether the dietary BITC-mediated boost of NK cell activity leads to suppression of carcinogenesis and metastasis in the TRAMP model of prostate cancer.

描述（由申请人提供）：自然杀伤（NK）细胞能够识别并杀死异常的（即，癌性和病毒感染的）细胞，而无需引发并且独立于靶的抗原呈递/组成。NK细胞已被证明可以防止癌症的发展。因此，相对安全但可增强NK细胞功能的药剂的鉴定和临床前/临床开发是高度期望的，其具有用于癌症化学预防的巨大转化应用。该项目旨在验证一种新的假设，即异硫氰酸苄酯（BITC）（许多可食用十字花科蔬菜的一种成分）预防前列腺癌至少部分是通过增强NK细胞功能介导的。这一假设源于我们的新的初步未发表的结果，显示BITC介导的增强NK细胞裂解活性在体外的相关浓度。此外，BITC介导的NK细胞裂解活性的增强与NK细胞产生的干扰素γ（IFN 3）和肿瘤坏死因子-α（TNF 1）的增加相关。尽管有这些令人鼓舞的结果，这些体外观察结果的体内意义尚不清楚。同样，BITC增强NK细胞活性的机制仍然难以捉摸。本申请的总体目标是使用前列腺癌作为疾病模型系统地探讨这些问题。关注前列腺癌的基本原理是基于以下考虑：（a）流行病学研究表明，十字花科蔬菜的饮食摄入量与前列腺癌风险之间存在负相关性，（B）最近的一项研究为在前列腺癌的TRAMP模型中通过NK细胞监测原发性肿瘤提供了重要的遗传证据。本提案的具体目的是（1）确定饮食BITC给药对体内NK细胞杀肿瘤活性的浓度效应关系，并深入了解该效应的机制，以及（2）确定饮食BITC介导的NK细胞活性增强是否导致TRAMP小鼠体内前列腺癌发生和转移的抑制。这些研究的积极结果将为临床试验奠定坚实的基础，以确定BITC介导的NK细胞活性增强和人类前列腺癌的发生。公共卫生相关性：我们发现膳食中的异硫氰酸苄酯（BITC）能够增强宿主NK细胞的功能。在这个项目中，我们将研究BITC摄入对宿主NK细胞杀肿瘤能力的体内方面。我们将首先确定饮食BITC给药对体内NK细胞杀肿瘤活性的浓度效应关系，并确定这种效应背后的机制。然后，我们将确定饮食BITC介导的NK细胞活性的增强是否导致前列腺癌的TRAMP模型中的癌发生和转移的抑制。