Mechanisms of prostate cancer prevention by lycopene

描述（由申请人提供）： 番茄红素是番茄的红色素，是一种膳食类胡萝卜素和一种有效的抗氧化剂，前瞻性和回顾性流行病学研究表明，它与男性前列腺癌发病率降低有关。我们对前列腺癌患者的初步临床研究表明，口服番茄红素可提高血清和前列腺中番茄红素的水平，并降低血清前列腺特异性抗原（PSA）。我们使用人前列腺癌细胞进行的初步细胞培养研究表明，番茄红素被雄激素敏感的前列腺癌细胞系LNCaP选择性地吸收并抑制其增殖，但对雄激素不敏感的前列腺癌细胞系DU 145和PC-3则没有。我们建议通过测量和比较雄激素敏感细胞系LNCaP、PZ-HPV-7和BPH-1（分别代表人前列腺癌、BPH和正常上皮细胞）以及雄激素不敏感前列腺癌细胞系DU 145、PC-3、C4-2B和CWR 22 Rv 1对番茄红素的摄取率来扩展这些细胞培养研究。 将确定番茄红素摄取率是否与这些细胞中增殖抑制成反比。为了阐明番茄红素作为抗增殖剂的作用机制，我们将测量番茄红素的亚细胞分布，然后使用ICAT定量蛋白质组学方法研究全球和亚细胞水平上蛋白质表达的变化。此外，将制备番茄红素亲和柱并用于筛选番茄红素敏感细胞的番茄红素受体或结合蛋白，其将使用基于质谱的蛋白质组学鉴定。番茄红素与雄激素受体的结合也将被研究。基于我们的观察，番茄红素降低前列腺癌患者的PSA水平，我们将研究细胞内PSA的表达和分泌是如何被培养物中番茄红素处理的前列腺细胞改变的;此外，我们将确定接受番茄红素补充剂的健康男性血清中的总PSA和游离PSA是否改变。最后，我们将确定两个潜在的治疗剂量的番茄红素，每天30毫克和每天60毫克的生物利用度和半衰期，使用稳定的同位素标记的番茄红素和HPLC串联质谱。这些人体研究将为未来研究番茄红素化学预防前列腺癌的临床试验设计提供重要信息。

DESCRIPTION (provided by applicant): Lycopene, the red pigment of the tomato, is a dietary carotenoid and a potent antioxidant that has been associated by prospective and retrospective epidemiological studies with a decreased incidence of prostate cancer in men. Our preliminary clinical studies in men with prostate cancer indicate that oral administration of lycopene elevates serum and prostate lycopene levels and reduces serum prostate specific antigen (PSA). Our preliminary cell culture studies using human prostate cancer cells show that lycopene is absorbed selectively by and inhibits the proliferation of the androgen sensitive prostate cancer cell line LNCaP but not the androgen-insensitive prostate cancer cell lines DU145 and PC-3. We propose to expand upon these cell culture studies by measuring and comparing the rates of lycopene uptake by the androgen-sensitive cell lines LNCaP, PZ-HPV-7, and BPH-1 (which represent human prostate cancer, BPH, and normal epithelial cells, respectively), and the androgen-insensitive prostate cancer cell lines DU145, PC-3, C4-2B, and CWR22Rv1. Whether the rates of lycopene uptake are inversely proportional to inhibition of proliferation in these cells will be determined. In order to clarify the mechanism of action of lycopene as an antiproliferative agent, we will measure the sub-cellular distribution of lycopene and then investigate changes in protein expression both globally and on the sub-cellular level using the ICAT quantitative proteomics methodology. In addition, a lycopene affinity column will be prepared and used to screen lycopene sensitive cells for a lycopene receptor or binding protein which will be identified using mass spectrometry-based proteomics. Lycopene binding to the androgen receptor will also be investigated. Based on our observation that lycopene reduces PSA levels in men with prostate cancer, we will investigate how the intracellular expression and secretion of PSA is altered by prostate cells treated with lycopene in culture; in addition, we will determine whether total PSA and percent-free PSA are altered in the serum of healthy men receiving lycopene supplements. Finally, we will determine the bioavailability and half-life of two potentially therapeutic doses of lycopene, 30 mg per day and 60 mg per day, using stable isotope labeled lycopene and HPLC-tandem mass spectrometry. These human studies will provide vital information for the design of future clinical trials investigating the chemoprevention of prostate cancer by lycopene.