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.

摘要 结肠癌是美国癌症相关死亡的第三大原因。 肿瘤的化疗耐药性（drug resistance）是化疗失败的主要原因， 结肠癌的死亡原因。化疗耐药的分子机制或治疗方法 使癌细胞对化学疗法重新敏感仍然是难以捉摸的。最近的研究表明，肠道微生物和 微生物代谢物在结肠癌的发展和进展中起着至关重要的作用， 化学抗性仍然未知。为此，我们研究了微生物的影响， 代谢产物尿石素A（UroA）对癌症化疗的影响。UroA是源自鞣花酸的微生物代谢产物 和鞣花单宁，它们是浆果和石榴的主要成分。我们的初步数据显示， UroA显著减少巨噬细胞中细菌诱导的炎症并保护其免受脂多糖的侵害 通过上调结肠上皮细胞中的连接蛋白诱导屏障功能障碍。更重要的是， 通过下调药物浓度，显著增加结肠癌细胞对5氟尿嘧啶（5 FU）的化疗增敏作用 转运蛋白和调节上皮-间充质转化（EMT）途径。组合疗法 显著减少结肠癌细胞的集落形成以及阻断癌细胞迁移。通过筛选 在UroA的几种新的结构类似物中，我们鉴定了一种有效的化合物UAS 03， 与UroA相比，增加了化学增敏活性。基于这些观察，我们假设， UroA和UAS 03通过调节药物浓度在5-FU疗法中作为化学增敏佐剂。 转运蛋白和癌症的干性。该提案的目标是确定微生物衍生的 UroA及其类似物UAS 03对结肠癌化疗，尤其是5 FU耐药癌症的作用。 在aim 1中，我们建议使用生物活性的生物素化UroA来鉴定UroA的分子靶点; UroA和UAS 03介导的5-FU耐药（5-FUR）结肠化疗增敏的分子机制 癌细胞在目标2中，我们将评估UroA或UAS 03与5 FU联合治疗 临床前结肠癌模型。我们将利用两种可植入的（由5 FUR结肠癌细胞产生的肿瘤） 和氧化偶氮甲烷-DSS模型。这些研究的成功完成将描绘监管 微生物代谢产物（UroA）介导的化学增敏机制，并为以下疾病提供更好的治疗选择 结肠癌