Synergy between phytochemicals for prostate cancer prevention

植物化学物质之间的协同作用预防前列腺癌

• 批准号: 7322669
• 负责人: JIN-RONG ZHOU
• 金额: $ 8.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322669
• 关键词: Androgens; Animal Model; Apoptosis; Biological; Biological Assay; Biological Markers; Cancer Cell Growth; Cell Proliferation; Cell physiology; Data; Dietary Component; Dose; Future; Gene Expression; Growth; Hand; Incidence; Inhibition of Cancer Cell Growth; LNCaP; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Modification; Molecular; Molecular Target; Nutritional; Pathway interactions; Phytochemical; Prevention; Preventive; Prostate; Prostatic Neoplasms; Research; Series; Sulforaphane; Testing; Toxic effect; Treatment Protocols; Tumor Angiogenesis; angiogenesis; base; cDNA Arrays; cancer type; design; in vivo; insight; neoplastic cell; prevent; prostate cancer prevention; silibinin; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): This pilot proposal is to evaluate the efficacy of the combination regimens of bioactive phytochemicals for prevention of prostate cancer progression by targeting simultaneously multiple steps involved in tumorigenesis. Prostate tumorigenesis involves in multiple critical steps, such as uncontrolled cancer cell growth and enhanced tumor angiogenesis. Dietary or nutritional modification has been considered to be an effective regimen for prevention and treatment of certain types of cancer including prostate cancer. Previous research has made considerable progress in identifying active dietary components. On the other hand, it has been recognized that cancer incidence and progression may not be reduced to the full extent possibly by single agents, and even promising agents usually show significant toxicity at efficacious doses. Therefore the combination of multiple agents based on differences in the mechanisms of cancer inhibition is expected to increase efficacy and/or reduce toxicity. Considerable data have indicated that combinations of agents that target cancer cell growth and tumor angiogenesis respectively may provide more effective regimens in an additive or a synergistic manner for prevention of prostate cancer progression. We have applied cellular function-based assays to identify the potent components for inhibition of cancer cell growth or suppression of angiogenesis, and have identified, from a group of active dietary components, sulforaphane and silybin as the most potent components for inhibition of prostate cancer cell growth and for suppression of angiogenesis respectively. Thus this pilot proposal is designed to test our hypothesis that the combination of sulforaphane and silybin may synergistically prevent the progression of prostate cancer. Specific Aim 1 is to determine the effect of sulforaphane and silybin combination on the growth of androgen-dependent and androgen- independent human prostate tumors in animal models. Orthotopic prostate tumor models for androgen- sensitive (LNCaP) and androgen-independent (PC-3) prostate cancers will be used to evaluate the preventive effects of sulforaphane and silybin combinations on prostate cancer progression. Specific Aim 2 is to identify biomarkers that are associated with and may be responsible for the possible synergistic effects of sulforaphane and silybin combinations in vivo. We will first determine a series of cellular markers that are associated with tumor cell proliferation, apoptosis and tumor angiogenesis (Aim 2a). In addition, cDNA microarray assays will be performed to identify potential molecular targets that may provide new insights into the molecular mechanisms of synergistic combinations (Aim 2b). We expect the proposed studies will allow us to verify possible synergistic effects between sulforaphane and silybin combinations on prevention of prostate cancer progression. Determinations of cellular biomarkers and identification of candidate molecular markers should provide sufficient preliminary data for further mechanism elucidation in the future RO1 proposal application.

描述（由申请人提供）： 该试点建议是通过同时靶向涉及肿瘤发生的多个步骤来评估生物活性植物化学物质联合方案对预防前列腺癌进展的功效。前列腺肿瘤发生涉及多个关键步骤，例如不受控制的癌细胞生长和增强的肿瘤血管生成。饮食或营养修饰被认为是预防和治疗某些类型的癌症在内的有效方案。先前的研究在确定活跃的饮食成分方面取得了长足的进步。另一方面，已经认识到，癌症的发生率和进展可能不会被单个药物降低到完全范围内，甚至有前途的药物通常在有效剂量时表现出明显的毒性。因此，根据癌症抑制机制的差异，多种药物的组合有望提高功效和/或降低毒性。大量数据表明，靶向癌细胞生长和肿瘤血管生成的药物的组合可能会以添加剂或协同方式提供更有效的方案，以预防前列腺癌的进展。我们已经采用了基于细胞功能的测定方法来识别抑制癌细胞生长或血管生成抑制的有效成分，并从一组活跃的饮食成分，硫烷和甲硅豆蛋白中鉴定为抑制前列腺癌细胞生长以及血管生成的抑制。因此，该试点建议旨在检验我们的假设，即磺胺素和甲硅烷基蛋白的结合可以协同阻止前列腺癌的进展。具体目的1是确定硫烷和硅豆蛋白组合对动物模型中雄激素依赖性和雄激素独立的人前列腺肿瘤生长的影响。用于雄激素敏感（LNCAP）和雄激素非依赖性（PC-3）前列腺癌的原位前列腺肿瘤模型将用于评估磺胺硫素和甲硅烷基蛋白组合对前列腺癌进展的预防作用。具体目的2是鉴定与体内磺胺和硅鸟蛋白组合的可能协同作用的生物标志物。我们将首先确定与肿瘤细胞增殖，凋亡和肿瘤血管生成有关的一系列细胞标记（AIM 2A）。此外，将进行cDNA微阵列测定，以确定可能为协同组合的分子机理提供新的见解的潜在分子靶标（AIM 2B）。我们预计拟议的研究将使我们能够验证磺胺硫烷和硅鸟蛋白组合对预防前列腺癌进展的可能协同作用。细胞生物标志物的测定和候选分子标记物的鉴定应提供足够的初步数据，以在未来的RO1建议应用中阐明进一步的机制。