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

• 批准号: 9416861
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9416861
• 关键词: 3T3-L1 Cells; Adenosine Monophosphate; Adipocytes; African American; Angiogenic Factor; Anti-inflammatory; Antineoplastic Agents; Biological Availability; Blood; CCL2 gene; Cells; Chemoprevention; Chemopreventive Agent; Chronic Disease; Clinical Trials; Coculture Techniques; Colon Carcinoma; Colorectal Cancer; Development; Diabetes Mellitus; Diet; 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; Population; Premalignant; 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/antagonist; malignant breast neoplasm; metastasis prevention; monocyte chemoattractant protein 1 receptor; mortality disparity; mouse model; neoplastic cell; novel; prostate cancer cell; prostate cancer prevention; protein expression; side effect; success; synthetic drug; tumor; tumor growth; tumor progression; tumor xenograft; 3T3-L1 Cells; Adenosine Monophosphate; Adipocytes; African American; Angiogenic Factor; Anti-inflammatory; Antineoplastic Agents; Biological Availability; Blood; CCL2 gene; Cells; Chemoprevention; Chemopreventive Agent; Chronic Disease; Clinical Trials; Coculture Techniques; Colon Carcinoma; Colorectal Cancer; Development; Diabetes Mellitus; Diet; 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; Population; Premalignant; 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/antagonist; malignant breast neoplasm; metastasis prevention; monocyte chemoattractant protein 1 receptor; mortality disparity; mouse model; neoplastic cell; novel; prostate cancer cell; prostate cancer prevention; protein expression; side effect; success; synthetic drug; tumor; tumor growth; tumor progression; tumor xenograft

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.

项目摘要/摘要 拟议项目的目的是确定天然产品组合的综合效果 Arctigenin和Green Tea（GT），有和没有MCP-1信号抑制剂504393（Rs）的预防和 治疗前列腺癌，尤其是在肥胖小鼠模型中。肥胖大大增加了挑战 预防癌症和治疗。肥胖促进肿瘤的发展和进展为侵略性形式 以及随后的转移，如大多数类型的癌症所观察到的，包括乳腺癌，结肠癌和前列腺癌。 另外，肥胖症会诱导肿瘤细胞对治疗药物的耐药性，从而导致治疗失败。 因此，在癌症化学预防和疗法方面的理想方法也应同时靶向肥胖症，理想情况下 以无毒的方式。但是，当前大多数化学治疗药物对肥胖的活性很小，并且 它们的功效通常受到副作用的限制。像GT这样的天然产品已被证明是有效的 多种慢性疾病，包括肥胖，2型糖尿病和癌症。我们在共同的体外证明了 培养肥胖模型是Arctigenin（一种新型的自然抗炎木质）与GT的组合 显着增强了前列腺癌细胞和脂肪细胞的抗增殖作用， 培养基中脂肪细胞分泌的IGF-1和VEGF的浓度降低。 Rs的组合，一个 选择性MCP-1受体CCR2抑制剂，带有阿氏菌素和GT导致前列腺癌细胞中消除了前列腺癌细胞 体外肥胖状态。拟议的项目将确认Arctigenin，GT的综合作用，有或没有 肥胖小鼠模型的体内喂养高脂饮食，该饮食模拟西方风格的饮食，低脂饮食 喂小鼠作为比较。具体目标1将确定阿氏素和GT在预防中的综合作用 转基因PTEN敲除小鼠中的前列腺癌。 AIM 2将研究Arcigenin的治疗作用， GT和RS抑制肿瘤生长和使用转基因和异种移植的转移预防 鼠标模型。 AIM 3将确定组合的分子机制，重点是 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 通过在癌症预防和 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 除了其功效之外，其潜在低成本，文化上可接受性和可行性的差异。此外 对于前列腺癌，GT和Arctigenin均表现出对其他类型癌症的功效，包括乳腺癌 和结直肠癌。因此，预计这种组合将为患者带来好处 多种癌症。