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

描述（由申请人提供）：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，主要是因为尚未建立类黄酮可能使患者受益的条件。虽然大量的数据，在体外和体内，证明槲皮素是一种有效的抗癌化合物，其作为化疗增敏剂的功能的知识是有限的，其在治疗结直肠癌患者的临床效用仍然未知。包括我们在内的细胞培养研究表明，槲皮素通过使细胞对药物和辐射敏感来增强治疗剂的作用。然而，槲皮素使恶性细胞对佐剂和/或放射疗法敏感的条件尚未建立用于完整动物。目前，5-氟尿嘧啶（5-FU）被广泛用于治疗晚期结肠癌;然而，这种药物对正常细胞有毒性。我们发现，在长期暴露，槲皮素单独或与抗癌药物，包括5-FU，显着和合作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5-FU和槲皮素之间的相互作用，这表明在这种相互作用的靶细胞的分子背景的重要作用。基于这些发现，我们假设槲皮素将通过以下方式增强5-FU对诱导和异种移植结直肠癌模型中具有野生型p53的细胞的活性：1）减小产生的肿瘤的大小和数量; 2）诱导程序性细胞死亡的分子效应物; 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在小鼠中的相互作用。将这些发现转化为人类，将有助于设计结肠癌的化疗方案，并导致更有利的临床结果。晚期结肠癌是很难治疗的。使用药理学剂量的黄酮类化合物使癌细胞对化疗剂和放射线敏感，通过减少杀死癌细胞所需的5-FU剂量，减少毒副作用，并防止耐药性的发展，将对癌症管理产生重大影响。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识别将从组合中受益的患者来决定个性化治疗。

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.