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)： 这项试验性的建议是通过同时针对参与肿瘤发生的多个步骤来评估生物活性植物化学物质组合方案预防前列腺癌进展的有效性。前列腺癌的发生涉及多个关键步骤，如癌细胞生长失控和肿瘤血管生成增强。饮食或营养修改一直被认为是预防和治疗某些类型癌症的有效方法，包括前列腺癌。以前的研究在确定有效的饮食成分方面取得了相当大的进展。另一方面，人们已经认识到，单一的药物可能不能完全减少癌症的发生和进展，即使是有希望的药物通常在有效剂量下也会显示出显著的毒性。因此，基于肿瘤抑制机制的不同，多种药物的联合使用有望提高疗效和/或降低毒性。大量数据表明，分别针对癌细胞生长和肿瘤血管生成的药物组合可能以添加或协同的方式提供更有效的方案来预防前列腺癌的进展。我们应用基于细胞功能的分析来确定抑制癌细胞生长或抑制血管生成的有效成分，并从一组有效的饮食成分中确定萝卜硫素和水飞蓟宾分别是抑制前列腺癌细胞生长和抑制血管生成的最有效成分。因此，这个试验性的建议是为了测试我们的假设，即萝卜硫素和水飞蓟宾的组合可以协同预防前列腺癌的进展。具体目的1是在动物模型中确定萝卜硫素和水飞蓟宾联合应用对雄激素依赖和雄激素非依赖性人前列腺肿瘤生长的影响。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癌模型将用于评估萝卜硫素和水飞蓟宾联合应用对前列腺癌进展的预防作用。具体目标2是确定与萝卜硫素和水飞蓟宾联合在体内可能产生的协同效应相关的生物标志物。我们将首先确定一系列与肿瘤细胞增殖、凋亡和肿瘤血管生成相关的细胞标志物(目标2a)。此外，还将进行cDNA微阵列分析，以确定潜在的分子靶点，这些靶点可能为协同组合的分子机制提供新的见解(目标2b)。我们期望拟议的研究将使我们能够验证萝卜硫素和水飞蓟宾在预防前列腺癌进展方面可能的协同作用。细胞生物标志物的测定和候选分子标志物的鉴定将为未来RO1提案的应用提供足够的初步数据，以进一步阐明机制。