Synergy between phytochemicals for prostate cancer prevention

这项试验性建议是为了评估生物活性植物化学物质组合方案的有效性。 通过同时针对涉及到的多个步骤来预防前列腺癌进展 肿瘤发生学。前列腺癌的发生涉及多个关键步骤，如癌细胞失控 生长和增强肿瘤血管生成。饮食或营养修改一直被认为是一种 预防和治疗某些类型癌症的有效方案，包括前列腺癌。上一首 在确定有效的饮食成分方面，研究已经取得了相当大的进展。另一方面，它有 人们已经认识到，癌症的发病率和进展可能不会完全减少，可能是通过 单一药物，甚至是有希望的药物，通常在有效剂量下表现出显著的毒性。因此， 基于癌症抑制机制差异的多种药物联合应用有望 提高疗效和/或降低毒性。大量数据表明，药物的组合 靶向癌细胞生长和肿瘤血管生成分别可能提供更有效的治疗方案 用于预防前列腺癌进展的添加剂或协同方式。我们已经应用了蜂窝 基于功能的分析以确定抑制癌细胞生长或抑制肿瘤细胞生长的有效成分 血管生成，并从一组有效的饮食成分中确定萝卜硫素和水飞蓟宾是 抑制前列腺癌细胞生长和抑制血管生成的最有效成分 分别进行了分析。因此，这个试点方案旨在测试我们的假设，即萝卜硫醚的组合 水飞蓟宾可以协同预防前列腺癌的进展。具体目标1是确定 萝卜硫素和水飞蓟宾联合应用对雄激素依赖和雄激素依赖小鼠生长的影响 人前列腺癌动物模型的研究。雄激素诱导的原位前列腺癌模型- 敏感性前列腺癌(LNCaP)和雄激素非依赖性前列腺癌(PC-3)将用于评估预防 萝卜硫素和水飞蓟宾联合应用对前列腺癌进展的影响。具体目标2是确定 与萝卜硫素可能的协同作用相关并可能对其起作用的生物标志物 和水飞蓟宾在体内的结合。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(目标2a)。此外，cDNA微阵列分析将 以确定潜在的分子靶点，可能提供对分子的新见解 协同组合的机制(目标2b)。我们希望拟议的研究将使我们能够核实 萝卜硫素与水飞蓟宾联合预防前列腺癌的可能协同作用 进步。细胞生物标记物的测定和候选分子标记的鉴定应 为未来RO1方案的应用进一步阐明机理提供充分的初步数据。

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.