Co-targeting obesity in prostate cancer chemoprevention and therapy

前列腺癌化学预防和治疗中的共同目标肥胖

基本信息

批准号：
10359726
负责人：
Piwen Wang
金额：
$ 35.88万
依托单位：
CHARLES R. DREW UNIVERSITY OF MED & SCI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10359726
关键词：
3T3-L1 Cells Adenosine Monophosphate Adipocytes African American population Angiogenic Factor Anti-Inflammatory Agents Antineoplastic Agents Biological Availability Blood CCL2 gene Cells Chemoprevention Chemopreventive Agent Chemoresistance Chronic Disease Clinical Trials Coculture Techniques Colon Carcinoma Colorectal Cancer Development Diabetes Mellitus Dose Epithelial FRAP1 gene Fat-Restricted Diet Fatty acid glycerol esters Goals Greater Burdock Green tea Growth Factor High Fat Diet Human Implant In Vitro Incidence Individual Inflammation Insulin-Like Growth Factor I Knockout Mice LNCaP Lignans Link Malignant Neoplasms Malignant neoplasm of prostate Modality Modeling Molecular Morbid Obesity Mus Natural Products Nature Neoplasm Metastasis Non obese Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity PTEN gene Pathway interactions Patients Pharmaceutical Preparations Phytochemical Prevention Preventive Prostate Prostate Cancer therapy Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Protein Kinase Regimen Resistance Seeds Severe Combined Immunodeficiency Signal Pathway Signal Transduction System Testing Therapeutic Therapeutic Effect Toxic effect Transgenic Organisms Treatment Failure Tumor Volume Tumor stage Vascular Endothelial Growth Factors Xenograft Model Xenograft procedure androgen sensitive anti-cancer arctigenin base cancer cell cancer chemoprevention cancer health disparity cancer prevention cancer therapy cancer type chemokine clinical practice cost cytokine density high risk improved in vivo inhibitor malignant breast neoplasm metastasis prevention monocyte chemoattractant protein 1 receptor mortality disparity mouse model neoplastic cell novel obese patients premalignant prostate cancer cell prostate cancer prevention protein expression side effect success synthetic drug tumor tumor growth tumor progression tumor xenograft western diet

项目摘要

Project Summary/Abstract The objective of the proposed project is to determine the combined effect of a combination of natural products arctigenin and green tea (GT), with and without a MCP-1 signaling inhibitor RS 504393 (RS) in prevention and treatment of prostate cancer particularly in obese mouse models. Obesity greatly increases the challenge in cancer prevention and treatment. Obesity promotes tumor development and progression to aggressive forms and subsequent metastasis, as observed in most types of cancer, including breast, colon, and prostate cancer. In addition, obesity induces resistance in tumor cells to therapeutic drugs, leading to the failure of treatments. Therefore, an ideal approach in cancer chemoprevention and therapy should co-target obesity as well, ideally in a non-toxic manner. However, most of the current chemotherapeutic drugs have little activity on obesity, and their efficacy is often limited by side effects. Natural product like GT has been shown to be effective against multiple chronic diseases, including obesity, type 2 diabetes, and cancer. We demonstrated in vitro in a co- culture obesity model that the combination of arctigenin, a novel natural anti-inflammatory lignan, with GT significantly enhanced the anti-proliferative effect in both prostate cancer cells and adipocytes, along with reduced concentrations of adipocytes-secreted IGF-1 and VEGF in culture medium. The combination of RS, a selective MCP-1 receptor CCR2 inhibitor, with arctigenin and GT led to elimination of prostate cancer cells in obese state in vitro. The proposed project will confirm the combined effect of arctigenin, GT, with and without RS in vivo in obese mouse models fed a high-fat diet which simulates the Western-style diet, with low-fat diet fed mice as comparison. Specific aim 1 will determine the combined effect of arctigenin and GT in prevention of prostate cancer in transgenic PTEN knockout mice. Aim 2 will investigate the therapeutic effect of arcigenin, GT and RS in inhibition of tumor growth and prevention of metastasis using both transgenic and xenograft mouse models. Aim 3 will identify the molecular mechanisms of the combination with a focus on their anti- angiogenic activities. The proposed project will make significant contributions to the control of prostate cancer by providing a highly effective and non-toxic modality through co-targeting obesity in cancer prevention and treatment. This combination will contribute to the elimination of prostate cancer incidence, mortality and cancer disparities with its potential low cost, culturally acceptability, and feasibility in addition to its efficacy. In addition to prostate cancer, both GT and arctigenin have shown efficacy against other types of cancer, including breast and colorectal cancer. Therefore this combination is anticipated to bring benefits to patients in treatment of multiple cancers.

项目概要/摘要拟议项目的目标是确定天然产品组合的综合效果牛蒡甙元和绿茶 (GT)，含或不含 MCP-1 信号抑制剂 RS 504393 (RS) 的预防和预防作用治疗前列腺癌，特别是肥胖小鼠模型。肥胖大大增加了挑战癌症的预防和治疗。肥胖促进肿瘤发展并进展为侵袭性形式以及随后的转移，正如在大多数类型的癌症中观察到的那样，包括乳腺癌、结肠癌和前列腺癌。此外，肥胖还会诱导肿瘤细胞对治疗药物产生耐药性，导致治疗失败。因此，癌症化学预防和治疗的理想方法也应该共同针对肥胖，理想情况下以无毒的方式。然而，目前大多数化疗药物对肥胖的作用甚微，且它们的功效常常受到副作用的限制。 GT 等天然产品已被证明可有效对抗多种慢性疾病，包括肥胖、2型糖尿病和癌症。我们在体外联合实验中证明了新型天然抗炎木脂素牛蒡子苷元与GT结合的培养肥胖模型显着增强前列腺癌细胞和脂肪细胞的抗增殖作用，同时培养基中脂肪细胞分泌的 IGF-1 和 VEGF 浓度降低。 RS 的组合，选择性 MCP-1 受体 CCR2 抑制剂，与牛蒡甙元和 GT 一起消除前列腺癌细胞体外肥胖状态。拟议的项目将确认牛蒡甙元、GT 在有或没有的情况下的综合效果肥胖小鼠模型中的RS体内模拟西式饮食的高脂肪饮食，以及低脂肪饮食喂小鼠作为比较。具体目标1将确定牛蒡甙元和GT的预防联合作用转基因 PTEN 敲除小鼠中前列腺癌的发生。目标2将研究argentinin的治疗效果， GT 和 RS 通过转基因和异种移植抑制肿瘤生长并预防转移鼠标模型。目标 3 将确定该组合的分子机制，重点关注其抗血管生成活性。拟议项目将为前列腺癌的控制做出重大贡献通过在癌症预防和预防中共同针对肥胖提供高效且无毒的方式治疗。这种组合将有助于消除前列腺癌的发病率、死亡率和癌症除了功效之外，其潜在的低成本、文化可接受性和可行性也存在差异。此外对于前列腺癌，GT 和牛蒡甙元均已显示出对其他类型癌症（包括乳腺癌）的功效和结直肠癌。因此，这种组合预计将为患者带来治疗益处多种癌症。