Co-targeting obesity in prostate cancer chemoprevention and therapy

项目摘要/摘要 拟议项目的目标是确定天然产品组合的综合效果。 牛至皂苷元和绿茶(GT)，加或不加单核细胞趋化蛋白-1信号抑制剂RS 504393(RS)预防和 前列腺癌的治疗，特别是在肥胖小鼠模型中。肥胖极大地增加了 癌症防治。肥胖促进肿瘤的发展和向侵袭性形式发展 以及随后的转移，如在大多数类型的癌症中观察到的，包括乳腺癌、结肠癌和前列腺癌。 此外，肥胖还会导致肿瘤细胞对治疗药物产生抗药性，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，理想情况下。 以无毒的方式。然而，目前的大多数化疗药物对肥胖几乎没有活性，而且 它们的疗效往往受到副作用的限制。像GT这样的天然产品已被证明对预防 多种慢性病，包括肥胖、2型糖尿病和癌症。我们在体外展示了一个联合- 新型天然抗炎木脂素牛至皂苷元与GT联合应用的培养肥胖模型 显著增强了前列腺癌和脂肪细胞的抗增殖作用，以及 降低培养上清液中脂肪细胞分泌的IGF-1和VEGF浓度。RS、a的组合 选择性单核细胞趋化蛋白-1受体CCR2抑制剂与牛至皂苷元和GT联合应用对前列腺癌细胞的杀伤作用 在体外处于肥胖状态。拟议的项目将证实牛至皂苷元、GT在有或没有的情况下的联合作用 在体肥胖小鼠模型中给予模拟西式饮食的高脂饮食，配合低脂饮食 给小鼠喂食作为对照。具体目标1将确定牛至皂苷元和GT在预防中的联合作用 在转基因PTEN基因敲除小鼠中前列腺癌的发生。目的2研究精氨酸的治疗作用， GT和RS在转基因和异种移植抑制肿瘤生长和防止转移中的作用 老鼠模型。目标3将确定这一组合的分子机制，重点是它们的抗 血管生成活动。拟议的项目将对前列腺癌的控制做出重大贡献。 通过提供一种高效和无毒的方式，通过共同瞄准肥胖来预防癌症和 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。 在潜在的低成本、文化可接受性和可行性以及其有效性方面存在差异。此外 对于前列腺癌，GT和牛膝皂苷元都显示出对包括乳腺癌在内的其他类型癌症的疗效 和结直肠癌。因此，这种结合有望给患者带来治疗的好处 多发性癌症。

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.