PQ-10: Microbial metabolite, Urolithin A is a potent immunomodulator and chemosensitizing adjuvant in treating colon cancer.

PQ-10：微生物代谢物尿石素 A 是治疗结肠癌的有效免疫调节剂和化疗增敏佐剂。

• 批准号: 9306482
• 负责人: Venkatakrishna Rao Jala
• 金额: $ 16.75万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-12 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306482
• 关键词: ABCG2 gene; Address; Adjuvant; Adopted; Affect; Americas; Anti-Inflammatory Agents; Anti-inflammatory; Area; Azoxymethane; Bacteria; Berry; Cancer Etiology; Cancer Model; Cell Survival; Cessation of life; Chemosensitization; Chemotherapy-Oncologic Procedure; Colitis; Colon; Colon Carcinoma; Combined Modality Therapy; Custom; Data; Development; Diet; Drug Efflux; Drug Regulations; Drug resistance; E-Cadherin; Ellagi-Tannins; Ellagic Acid; Epithelial; Epithelial Cells; Failure; Fluorouracil; Functional disorder; Genes; Goals; High-Throughput Nucleotide Sequencing; Immunomodulators; Inflammation; Inflammatory disease of the intestine; Interleukin-6; Knowledge; Lipopolysaccharides; Malignant Neoplasms; Mediating; Mesenchymal; Methods; Modeling; Molecular; Molecular Target; Mus; Oral Administration; P-Glycoprotein; Pathway interactions; Pharmaceutical Preparations; Play; Pomegranate; Population; Pre-Clinical Model; Proteins; Resistance; Role; Sodium Dextran Sulfate; Symbiosis; TLR4 gene; TNF gene; Therapeutic; Therapeutic Effect; Treatment Efficacy; United States; Xenograft Model; Xenograft procedure; analog; base; cancer cell; cancer therapy; carcinogenicity; cell motility; chemosensitizing agent; chemotherapy; clinically relevant; colon cancer cell line; colon cancer patients; colon tumorigenesis; gut microbiota; immunoregulation; improved; indexing; innovation; iron metabolism; macrophage; microbial; microbiota; mortality; mouse model; neoplastic cell; novel; occludin; pre-clinical; response; screening; stemness; synergism; three dimensional cell culture; translational impact; tumor

Abstract Colon cancer is the third leading cause of cancer related deaths in United States of America. Chemoresistance (drug resistance) of tumors is the primary reason for the failure of chemotherapy and the major cause of mortality in colon cancer. The molecular mechanisms involved in chemoresistance or approaches to resensitize cancer cells to chemotherapy remain elusive. Recent studies suggest that gut microbiota and microbial metabolites play a crucial role in the development and progression of colon cancer but their role in chemoresistance remains unknown. Towards this goal, we investigated the influence of commensal microbial metabolite, Urolithin A (UroA) on cancer chemotherapy. UroA is a microbial metabolite derived from ellagic acid and ellagitannins, which are major components of berries and pomegranate. Our preliminary data showed that UroA significantly reduced bacteria induced inflammation in macrophages and protected from lipopolysaccharide induced barrier dysfunction by upregulating junctional proteins in colon epithelial cells. More importantly, UroA significantly increased the chemosensitization of colon cancer cells to 5florouracil (5FU) by down regulating drug transporters and modulating epithelial-mesenchymal transition (EMT) pathways. The combination therapy significantly reduced colony formation of colon cancer cells as well as blocked cancer cell migration. By screening several novel structural analogues of UroA, we have identified a potent compound, UAS03, which displayed increased chemosensitizing activities compared to UroA. Based on these observations, we hypothesize that ‘UroA and UAS03 act as chemosensitizing adjuvants in 5-FU therapies through regulation of drug transporters and cancer stemness. The goal of the proposal is to determine the effects of microbial derived metabolites (UroA and its analogue UAS03) on colon cancer chemotherapy, especially 5FU resistant cancers. In aim1, we propose to identify the molecular target of UroA using bioactive biotinylated UroA; to determine the molecular mechanisms of UroA and UAS03 mediated chemosensitization of 5FU-resistance (5FUR) colon cancer cells. In aim 2, we will evaluate the therapeutic efficacies of UroA or UAS03 in combination with 5 FU in preclinical colon cancer models. We will utilize both implantable (tumors generated by 5FUR colon cancer cells) and azoxymethane-DSS models. The successful completion of these studies will delineate regulatory mechanisms of microbial metabolite (UroA) mediated chemosensitization and offer better therapeutic options for colon cancer.

抽象的 结肠癌是美国与癌症相关死亡的第三大主要原因。 肿瘤的化学耐药性（耐药性）是化学疗法失败的主要原因 结肠癌死亡率的原因。参与化学耐药或方法的分子机制 将癌细胞恢复到化学疗法仍然难以捉摸。最近的研究表明，肠道菌群和 微生物代谢产物在结肠癌的发展和发展中起着至关重要的作用 化学抗性仍然未知。为了实现这一目标，我们研究了共生微生物的影响 代谢产物，尿石A（UROA）在癌症化疗中。 UROA是一种源自椭圆酸的微生物代谢产物 和Ellagitannins，它们是浆果和石榴的主要成分。我们的初步数据表明 UROA显着降低了细菌诱导的巨噬细胞注射并免受脂多糖的保护 通过上调结肠上皮细胞中的连接蛋白引起的屏障功能障碍。更重要的是，Uroa 通过降低调节药 转运蛋白和调节上皮 - 间质转变（EMT）途径。组合疗法 显着降低了结肠癌细胞的落形成以及癌细胞迁移的阻塞。通过筛选 UROA的几种新型结构类似物，我们已经确定了一个潜在的化合物UAS03，该化合物显示了 与UROA相比，化学敏化活性增加。基于这些观察，我们假设 'UROA和UAS03通过调节药物在5-FU疗法中充当化学敏化调节剂 转运蛋白和癌症。该提案的目的是确定微生物衍生的影响 结肠癌化学疗法，尤其是5FU抗药性癌症的代谢产物（UROA及其类似UAS03）。 在AIM1中，我们建议使用生物活性生物素化的UROA鉴定UROA的分子靶标。确定 UROA和UAS03介导的5FU抗性（5FUR）结肠的化学敏化的分子机制 癌细胞。在AIM 2中，我们将评估UROA或UAS03的治疗效率与5 fu 临床前结肠癌模型。我们将利用两种植入（由5fur结肠癌细胞产生的肿瘤） 和偶氮甲烷-DSS模型。这些研究的成功完成将描述监管 微生物代谢产物（UROA）介导的化学敏化的机制，为更好的治疗选择提供 结肠癌。