Indole-3-carbinol derivatives with enhanced chemopreventive activities

描述(由申请人提供)： 在肿瘤发生过程中，癌细胞通过结构性地上调与细胞增殖和生存相关的多个信号通路来克服基因组的不稳定性。这种肿瘤的异质性给癌症患者的临床管理和有效的预防和治疗策略的发展带来了挑战。解决这一问题的合理策略是同时靶向不同的分子异常，并使用有效的多效剂来改善临床结果。这一基本原理构成了我们对吲哚-3-甲醇进行结构优化以开发具有多效性机制的有效抗肿瘤药物的分子基础，最终产生了一种酸稳定的衍生物OSU-A9。OSU-A9显示出100倍的抗肿瘤活性，并且在靶向癌细胞中的多个信号靶点方面的效果惊人地相似。尽管有这种复杂的机制模式，非恶性细胞对OSU-A9的抗增殖作用不太敏感。因此，该项目测试了我们的假设，即使用一种针对与肿瘤发生和肿瘤进展相关的多个信号通路的多效性药物代表着一种有效的癌症预防策略，其目的有两个。目标1是继续OSU-A9的结构修饰和最优衍生物的机理验证。将产生两个系列的衍生物，其中OSU-A9的吲哚环被具有不同立体电子性质的取代基取代。我们预计这一目标将产生3个最佳的衍生物，具有低到低于5M的抗肿瘤活性，用于机制验证和体内测试。目的2评价优化的OSU-A9衍生物在转基因小鼠前列腺癌(TRAMP)模型中阻断前列腺癌形成的体内效果。我们假设最优的OSU-A9衍生物可以在体内以临床可获得的浓度阻止前列腺癌的发生。这一目标包括三个部分。首先，确定OSU-A9及其最佳衍生物在裸鼠体内的口服最大耐受量。二是确定这些药物在PC-3异种移植瘤模型中的体内疗效和潜在毒性。三是在TRAMP模型中评价它们的化学预防活性。我们预计，这些最佳的衍生物将提供相当大的优势，相对于吲哚-3-甲醇和其他植物化学物质，在培育潜在的成功策略，以阻止或延缓前列腺癌的发生和/或肿瘤的进展。公共卫生相关性：项目叙述在男性中，前列腺癌是最常见的被诊断的癌症，也是癌症死亡的第二大原因。我们的总体研究目标是开发针对前列腺癌细胞中特定分子和细胞缺陷的新型药物，这使得这种疾病的临床管理和预防策略的制定具有挑战性。我们预计，该项目最终将产生阻止或延缓前列腺癌发展和/或进展的新药。

DESCRIPTION (provided by applicant): During the course of tumorigenesis, cancer cells overcome genomic instability by constitutively up-regulating multiple signaling pathways pertinent to cell proliferation and survival. This tumor heterogeneity poses challenges to the clinical management of cancer patients and to the development of effective preventive and therapeutic strategies. A rational strategy to address this issue is the concomitant targeting of different molecular abnormalities with a potent pleiotropic agent to improve clinical outcomes. This rationale constitutes the molecular basis for our structural optimization of indole-3-carbinol to develop potent antitumor agents with pleiotropic modes of mechanism, which has culminated in the generation of an acid-stable derivative, OSU-A9. OSU-A9 exhibits a 100-fold higher antitumor activity and striking similarities in its effects on targeting multiple signaling targets in cancer cells. Despite this complex mode of mechanisms, nonmalignant cells were less susceptible to the antiproliferative effect of OSU-A9. This project thus tests our hypothesis that use of a pleiotropic agent that targets multiple signaling pathways associated with oncogenesis and tumor progression represents an effective strategy for cancer prevention, of which the aim is twofold. Aim 1 is to continue the structural modification of OSU-A9 and mechanistic validation of optimal derivatives. Two series of derivatives will be generated, in which the indole ring of OSU-A9 is substituted with substituents with different stereoelectronic properties. We expect that this Aim will generate 3 optimal derivatives with low to sub-5M potency in antitumor activity for mechanistic validation and in vivo testing. Aim 2 is to assess the in vivo efficacy of the optimal OSU-A9 derivatives on blocking prostate tumorigenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We hypothesize that the optimal OSU-A9 derivative can block prostate tumorigenesis in vivo at clinically attainable concentrations. This Aim consists of three parts. First is to determine the oral maximum tolerated doses of OSU-A9 and its optimal derivatives in nude mice. Second is to determine the in vivo efficacies and to identify potential toxicities of these agents in the PC- 3 xenograft tumor model. Third is to evaluate their chemopreventive activities in the TRAMP model. We expect that these optimal derivatives will provide considerable advantages relative to indole-3-carbinol and other phytochemicals in fostering potentially successful strategies to block or delay prostate tumorigenesis and/or tumor progression. PUBLIC HEALTH RELEVANCE: Project narrative In men, prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death. Our overall research goal is to develop novel agents that target the specific molecular and cellular defects in prostate cancer cells that make the clinical management and development of preventive strategies for this disease so challenging. We expect that this project will ultimately yield new drugs that will block or delay the development and/or the progression of prostate cancer.