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

番茄红素

• 批准号: 7496103
• 负责人: Xiaolin Zi
• 金额: $ 15.26万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496103
• 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）：晚期前列腺癌患者具有显着的长期发病率。尽管缺乏临床数据证明其功效，但包括番茄红素在内的膳食补充剂的使用最近在这些患者中越来越受欢迎。由于多西紫杉醇已成为激素难治性前列腺癌患者的一线化疗药物，因此需要评估番茄红素与多西紫杉醇化疗联合的疗效和安全性。虽然临床前研究表明番茄红素可以作为强抗氧化剂来改善许多化疗药物的毒性作用，但番茄红素是否会增强或干扰基于多西他赛的化疗的抗肿瘤活性仍不清楚。我们的初步数据表明，生理浓度的番茄红素可以增强多西紫杉醇降低 PCa 细胞系体外活力的功效。因此，我们假设番茄红素和多西紫杉醇在抑制体内肿瘤生长方面具有协同作用或相加作用。我们还证明番茄红素对PCa细胞系生长的抑制作用与其胰岛素生长因子-I受体（IGF-IR）的水平密切相关，稳定表达高水平IGF-IR的LNCaP细胞约对番茄红素生长抑制作用的敏感性比亲本 LNCaP 细胞高 400 倍。因此，我们假设 PCa 细胞中 IGF-IR 的表达可以作为番茄红素和多西紫杉醇组合对 PCa 敏感性的指标。我们的具体目标有两个：首先，我们将确定番茄红素、多西紫杉醇或两者的组合在异种移植激素难治性 PCa 模型中抑制肿瘤生长的能力；其次，我们将生成一对过表达或抑制 IGF-IR 的转基因前列腺癌细胞系，并评估 IGF-IR 及其主要下游事件 AKT 和 ERK1/2 的参与以及番茄红素的综合作用和多西他赛。我们的长期目标是回答当前临床实践中的一个重要问题：接受多西紫杉醇化疗的前列腺癌患者是否应该服用番茄红素补充剂？如果我们提出的动物实验产生积极结果，则将在 R01 申请中提出在前列腺癌患者中进行多西紫杉醇和番茄红素组合的研究性临床试验。这些研究获得的结果也可能提供证据表明，在临床实践中与主流疗法相结合时，通过无毒的饮食方法（例如番茄红素补充剂）靶向 IGF-IR 可以有效且安全地治疗前列腺癌。多西紫杉醇已成为激素难治性前列腺癌患者的一线化疗，并且这些患者普遍使用番茄红素补充剂。我们提议在动物模型中检查番茄红素是否可以增强或干扰多西紫杉醇的抗肿瘤功效，以及番茄红素是否可以用作前列腺癌联合治疗中靶向IGF-IR的无毒饮食方法。