Lycopene & Docetaxel in Prostate Cancer: An IGF-I Receptor Targeting Approach

番茄红素

• 批准号: 7297046
• 负责人: Xiaolin Zi
• 金额: $ 18.3万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7297046
• 关键词: Adverse effects; Androgens; Animal Experiments; Animal Model; Antioxidants; Apoptosis; CWR22Rv1; Cancer Model; Cancer Patient; Cell Line; Cells; Clinical; Clinical Data; Clinical Trials; Complement component C1s; Complementary and alternative medicine; DU145; Data; Development; Diet; Dose; Event; Family member; Fibrinogen; Friends; Future; Goals; Growth; Growth Factor; Guidelines; Health; Hormonal; Hormones; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Internet; LNCaP; Lead; Malignant neoplasm of prostate; Mediating; Mitogen-Activated Protein Kinase 3; Morbidity - disease rate; Mus; Nude Mice; Numbers; PC3 cell line; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physicians; Physiological; Prostate Cancer therapy; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; RNA Interference; Recommendation; Refractory; Regulation; Risk; Role; Safety; Serum; Societies; Somatomedins; Standards of Weights and Measures; Stream; Therapeutic; Tomatoes; Toxic effect; Treatment Efficacy; Tumor Volume; Week; Weight; Xenograft procedure; base; cancer cell; chemotherapy; day; dietary supplements; docetaxel; efficacy evaluation; feeding; hormone refractory prostate cancer; implantation; improved; in vivo; lycopene; male; men; oncology; preclinical study; subcutaneous; tumor; tumor growth

DESCRIPTION (provided by applicant): Advanced prostate cancer patients have significant long-term morbidity. Uses of dietary supplements including lycopene have recently gained popularity in these patients despite the paucity of clinical data to demonstrate their efficacy. As docetaxel has become the first line chemotherapy for patients with hormonal refractory prostate cancer, the efficacy and safety of lycopene in combination with docetaxel-based chemotherapy needs to be evaluated. While preclinical studies have suggested that lycopene could be used as a strong antioxidant for ameliorating the toxic effects of many chemotherapeutical agents, whether lycopene will enhance or interfere with the anti-tumor activity of docetaxel-based chemotherapy remains unknown. Our preliminary data has demonstrated that lycopene at physiological concentrations can potentiate the efficacy of docetaxel in reducing the viability of PCa cell lines in vitro. Thus, we hypothesize that lycopene and docetaxel have synergy or addition in the inhibition of tumor growth in vivo. We also have demonstrated that the inhibitory effect of lycopene on the growth of PCa cell lines is closely related to their levels of insulin growth factor-I receptor (IGF-IR), and that LNCaP cells stably expressing high level of IGF-IR are about 400 fold more sensitive to the growth inhibitory effect of lycopene than parental LNCaP cells. We therefore hypothesize that the expression of IGF-IR in PCa cells can serve as an indicator for the sensitivity of lycopene and docetaxel combination against PCa. Our specific aims are two folds: First, we will determine the abilities of lycopene, docetaxel or combination of both to inhibit tumor growth in xenograft hormone refractory PCa models; Second, we will generate pairs of genetically modified prostate cancer cell lines with either overexpression or suppression of IGF-IR and evaluate the involvement of IGF-IR and its main down-stream events, AKT and ERK1/2, with the combined effects of lycopene and docetaxel. Our long term goal is to answer an important question in current clinical practices: should prostate cancer patients undergoing docetaxel-base chemotherapy take lycopene supplements? If a positive result is produced in our proposed animal experiments, an investigative clinical trial of docetaxel and lycopene combination in prostate cancer patients will be proposed in an R01 application. The results obtained from these studies may also provide evidence that targeting IGF-IR by a non-toxic, dietary approach (e.g. lycopene supplement) would be effective and safe in treatment of prostate cancer when combined with main-stream therapies in clinical practices. Docetaxel has become the first line chemotherapy for patients with hormonal refractory prostate cancer, and use of lycopene supplements is popular by these patients. We proposed to examine whether lycopene can enhance or interfere with the anti-tumor efficacy of docetaxel in animal models, and whether lycopene can be used as a non-toxic, dietary approach for targeting IGF-IR in combined therapies for prostate cancer.

描述（由申请人提供）：晚期前列腺癌患者的长期发病率显着。尽管临床数据很少证明其疗效，但包括番茄红素在内的饮食补充剂的使用最近在这些患者中越来越受欢迎。由于多西他赛已成为激素难治性前列腺癌患者的第一线化疗，因此需要评估番茄红素与基于多西他赛的化学疗法结合使用的疗效和安全性。尽管临床前研究表明，番茄红素可以用作强大的抗氧化剂来改善许多化学治疗剂的毒性作用，但番茄红素是否会增强或干扰基于多西他赛的化学疗法的抗肿瘤活性。我们的初步数据表明，生理浓度下的番茄红素可以增强多西他赛在降低体外PCA细胞系的生存力方面的疗效。因此，我们假设番茄红素和多西他赛在体内抑制肿瘤生长方面具有协同或添加。我们还证明，番茄红素对PCA细胞系生长的抑制作用与它们的胰岛素生长因子-I受体（IGF-IR）的水平密切相关，并且LNCAP细胞稳定地表达IGF-IR的高水平的IGF-IR稳定性比乳液LNCAP细胞的生长抑制作用更为敏感。因此，我们假设IGF-IR在PCA细胞中的表达可以作为番茄红素和多西他赛对PCA的敏感性的指标。我们的具体目的是两个倍：首先，我们将确定番茄红素，多西他赛或两者组合抑制异种移植激素难治性PCA模型中肿瘤生长的能力；其次，我们将生成具有过表达或抑制IGF-IR的基因修饰的前列腺癌细胞系对，并评估IGF-IR及其主要的下游事件AKT和ERK1/2的参与，并与番茄红素和多西他的综合作用。我们的长期目标是在当前的临床实践中回答一个重要的问题：前列腺癌患者是否应该接受多西他赛基碱化疗服用番茄红素补充剂？如果在我们提出的动物实验中产生阳性结果，将在R01应用中提出对前列腺癌患者中多西他赛和番茄红素组合的研究临床试验。从这些研究中获得的结果还可以提供证据表明，通过一种无毒的饮食方法（例如番茄红素补充剂）靶向IGF-IR在临床实践中与主流疗法结合使用时，将有效且安全地治疗前列腺癌。多西他赛已成为荷尔蒙难治性前列腺癌患者的第一线化学疗法，使用番茄红素补充剂是这些患者流行的。我们建议检查番茄红素是否可以增强或干扰动物模型中多西他赛的抗肿瘤功效，以及是否可以将番茄红素用作靶向IGF-IR在前列腺癌联合治疗中靶向IGF-IR的一种无毒的饮食方法。