Co-targeting obesity in prostate cancer chemoprevention and therapy

项目总结/摘要 拟议项目的目标是确定一种天然产品组合的综合效应 牛蒡子苷元和绿色茶（GT），有和没有MCP-1信号传导抑制剂RS 504393（RS）， 治疗前列腺癌，特别是在肥胖小鼠模型中。肥胖大大增加了 癌症预防和治疗。肥胖促进肿瘤发展和进展为侵袭性形式 以及随后的转移，如在大多数类型的癌症中所观察到的，包括乳腺癌、结肠癌和前列腺癌。 此外，肥胖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，理想的癌症化学预防和治疗方法应该同时针对肥胖， 以无毒的方式。然而，目前大多数化疗药物对肥胖症的活性很小， 它们的功效常常受到副作用的限制。天然产品如GT已被证明是有效的， 多种慢性疾病，包括肥胖、2型糖尿病和癌症。我们在体外实验中证明了， 牛蒡子苷元是一种新型的天然抗炎木脂素， 显著增强前列腺癌细胞和脂肪细胞的抗增殖作用，沿着 降低培养基中脂肪细胞分泌的IGF-1和VEGF的浓度。RS的组合， 选择性MCP-1受体CCR 2抑制剂与牛蒡子苷元和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子苷元，GT，与和不 RS肥胖小鼠模型在体内喂以高脂饮食，其中模拟西式饮食，配合低脂饮食 喂养的小鼠作为对比。具体目标1将确定牛蒡子苷元和GT在预防中的联合作用 在转基因PTEN敲除小鼠中前列腺癌的发生率。目的2探讨arcigenin对糖尿病的治疗作用， GT和RS在转基因和异种移植中抑制肿瘤生长和预防转移的作用 小鼠模型。目的3将确定联合的分子机制，重点是它们的抗- 血管生成活性。拟议的项目将为控制前列腺癌做出重大贡献 通过在癌症预防中共同靶向肥胖提供高效无毒的方式， 治疗这种结合将有助于消除前列腺癌的发病率，死亡率和癌症 除了其功效之外，其潜在的低成本、文化上的可接受性和可行性也是不平等的。此外 对于前列腺癌，GT和牛蒡子苷元都显示出对其他类型的癌症，包括乳腺癌， 和结肠直肠癌。因此，预期该组合给治疗以下疾病的患者带来益处： 多种癌症

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.