Quercetin as an enhancer of the efficacy of 5-FU in mouse models of colon cancer

槲皮素作为结肠癌小鼠模型中 5-FU 功效的增强剂

• 批准号: 8628386
• 负责人: Temesgen Samuel
• 金额: $ 11.03万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628386
• 关键词: Adjuvant; Adverse effects; Animals; Antineoplastic Agents; Apoptosis; Azoxymethane; Cancer Patient; Carcinogens; Categories; Cell Culture Techniques; Cells; Clinic; Clinical; Colon Carcinoma; Colorectal Cancer; Data; Development; Dose; Drug resistance; Drug usage; Enhancers; Favorable Clinical Outcome; Flavonoids; Fluorouracil; Goals; Grant; Human; In Vitro; Knowledge; Laboratories; Lead; Luciferases; Malignant Neoplasms; Measures; Molecular; Molecular Profiling; Mus; Normal Cell; Patients; Pharmaceutical Preparations; Property; Protein p53; Quercetin; Radiation; Radiation therapy; Regimen; Research; Research Personnel; Role; TP53 gene; Therapeutic; Therapeutic Agents; Time; Translating; Xenograft Model; Xenograft procedure; advanced disease; base; cancer cell; chemosensitizing agent; chemotherapeutic agent; design; drug efficacy; in vivo; in vivo imaging; killings; molecular marker; mouse model; neoplastic; preclinical study; prevent; public health relevance; response; treatment effect; tumor; tumor growth; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): The anticancer properties of the flavonoid quercetin have not been effectively translated from the laboratory to the clinic, mainly because the conditions under which the flavonoid may benefit patients have not been established. Although extensive data, derived in vitro and in vivo, demonstrate that quercetin is a potent anticancer compound, knowledge of its function as a chemosensitizer is limited, and its clinical utility in treatment of colorectal cancer patients remains unknown. Cell culture studies, including ours, indicate that quercetin potentiates the effects of therapeutic agents by sensitizing the cells to drugs and to radiation. However, the conditions under which quercetin sensitize malignant cells to adjuvant and/or radiation therapies are yet to be established for intact animals. Currently, 5-fluorouracil (5-FU) is widely used to treat advanced colon cancer; however, this agent is toxic to normal cells. We showed that, upon extended exposure, quercetin alone or in combination with anticancer drugs, including 5-FU, substantially and cooperatively inhibited proliferation of colon cancer cells. We also found that the p53 status of colon cancer cells markedly altered the interaction between 5-FU and quercetin, suggesting an essential role for the molecular background of the target cells in such interactions. Based on these findings, we hypothesize that quercetin will enhance the activity of 5-FU on cells with wild-type p53 in both induced and xenograft models of colorectal cancer by: 1) reducing the size and number of arising tumors; 2) inducing molecular effectors of programmed cell death; and 3) suppressing proliferation of cancer cells. The optimum conditions for quercetin to potentiate the efficacy of 5-FU in mice will be established. Therefore, the goal of this study is to determine the interaction between quercetin and 5-FU in mice. Translated to humans, the findings will aid in designing the chemotherapeutic regimens for colon cancer and lead to more favorable clinical outcomes. Advanced colon cancer is difficult to treat. The use of pharmacological doses of flavonoids to sensitize cancer cells to chemotherapeutic agents and radiation would have a great impact on cancer management by reducing the dose of 5-FU needed to kill cancer cells, by reducing toxic side effects, and by preventing development of drug resistance. Additionally, determination of the role of p53 in the drug-flavonoid interaction would aid in decisions for personalized therapy by identifying patients who will benefit from the combination.

描述（申请人提供）：类黄酮槲皮素的抗癌特性尚未有效地从实验室转化为临床，主要是因为尚未确定类黄酮使患者受益的条件。尽管体外和体内获得的大量数据表明槲皮素是一种有效的抗癌化合物，但对其作为化学增敏剂的功能的了解有限，并且其在治疗结直肠癌患者中的临床效用仍然未知。细胞培养研究（包括我们的研究）表明，槲皮素通过使细胞对药物和辐射敏感来增强治疗药物的效果。然而，对于完整动物来说，槲皮素使恶性细胞对辅助和/或放射疗法敏感的条件尚未确定。目前，5-氟尿嘧啶（5-FU）广泛用于治疗晚期结肠癌；然而，这种药物对正常细胞有毒。我们发现，长期接触槲皮素或与抗癌药物（包括 5-FU）联合使用，可显着协同抑制结肠癌细胞的增殖。我们还发现结肠癌细胞的 p53 状态显着改变了 5-FU 和槲皮素之间的相互作用，表明靶细胞的分子背景在这种相互作用中发挥着重要作用。基于这些发现，我们假设槲皮素将通过以下方式增强结直肠癌诱导模型和异种移植模型中野生型 p53 细胞上 5-FU 的活性：1）减少肿瘤的大小和数量； 2）诱导程序性细胞死亡的分子效应； 3)抑制癌细胞的增殖。将建立槲皮素在小鼠中增强 5-FU 功效的最佳条件。因此，本研究的目的是确定槲皮素和 5-FU 在小鼠体内的相互作用。转化为人类后，这些发现将有助于设计结肠癌的化疗方案，并带来更有利的临床结果。晚期结肠癌很难治疗。使用药理学剂量的类黄酮来提高癌细胞对化疗药物和放射的敏感性，可以减少杀死癌细胞所需的 5-FU 剂量、减少毒副作用以及防止耐药性的产生，从而对癌症治疗产生重大影响。此外，确定 p53 在药物-类黄酮相互作用中的作用将有助于通过确定将从组合中受益的患者来制定个性化治疗决策。