Colorectal cancer chemoprevention with phytochemical combinations

描述（由申请人提供）：结直肠癌（CRC）在全球范围内高度流行，死亡率高。 活性膳食化学品目前正在临床试验中作为补充癌症预防剂进行探索。 我们的长期目标是阐明 代谢对有前途的植物化学物质的药代动力学和相关临床疗效的影响。 重要的是，虽然植物化学物质的组合越来越多地显示出比单独的单一药剂更有效，但这种协同作用的机制尚不清楚。 具体而言，迄今为止还没有关于膳食植物化学品组合如何调节葡萄糖醛酸化酶-即尿苷二磷酸葡萄糖醛酸转移酶（哺乳动物UGT;人UGT，小鼠UGT）的研究。 该建议是基于植物化学组合协同诱导哺乳动物UGT的假设。 因此，植物化学组合可能比单一药剂更有效地抑制致癌物。 为此，提出了两个具体的目标：1）评价UGT诱导植物化学品单独和组合。 基于单个抗增殖IC 50的比例的植物化学组合反式白藜芦醇+姜黄素和反式白藜芦醇+白杨素将 测试并与单独的每种植物化学物质进行比较。 将在转化的人肠Caco-2细胞中评价人UGT的诱导，而将在小鼠肠上皮正常和肿瘤前（YAMC和IMCE）细胞以及小鼠肝ImHep细胞中评价小鼠ugts。 将在正常C57 BL小鼠模型中体内测试在上述A部分中产生最显著结果的组合。 2)评估UGT诱导作为植物化学组合的化学预防机制。 将在小鼠中评价植物化学组合的协同UGT诱导是否是增强化学预防的机制。 将在葡聚糖硫酸钠+2-氨基-1-甲基-6-苯基咪唑并[4，5-B]吡啶（DSS/PhIP）结肠腺癌小鼠模型中测试具有来自目标1的最高预测功效的组合，并测量异常隐窝病灶（ACF）、肿瘤大小/频率和ugt诱导。 将化学预防功效与已知的CRC预防剂塞来昔布进行比较。 从拟议的目标的数据将形成未来的研究的基础，以评估额外的代谢酶和转运蛋白的植物化学物质调制。 公共卫生相关性：该项目侧重于使用有前景的膳食化学品预防结直肠癌。 拟议的研究将评估饮食化学品组合在增加新陈代谢方面的功效，从而更好地解毒致癌物质。 用来自食物的安全化学物质预防结直肠癌有望显着降低这种疾病的负担。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is highly prevalent worldwide and exhibits high mortality. Active dietary chemicals are currently being explored as complementary cancer preventive agents in clinical trials. Our long-term goal is to elucidate the impact of metabolism on the pharmacokinetics and associated clinical efficacy of promising phytochemicals. Importantly, while combinations of phytochemicals are increasingly shown to be more efficacious than single agents alone, mechanisms underlying this synergy are not understood. Specifically, there is no research to date on how dietary phytochemical combinations modulate glucuronidating enzymes - i.e. uridine diphosphoglucuronosyltransferases (mammalian UGT; human UGT, mouse ugt). This proposal is based on the hypothesis that phytochemical combinations synergistically induce mammalian UGTs. Phytochemical combinations might thus more effectively inactivate carcinogens than single agents. Toward this, two specific aims are proposed: 1) Evaluate UGT induction by phytochemicals alone and in combination. Phytochemical combinations trans-resveratrol + curcumin and trans-resveratrol + chrysin in ratios based on individual antiproliferative IC50s will be tested and compared against each phytochemical alone. Induction of human UGTs will be evaluated in transformed human intestinal Caco-2 cells, while mouse ugts will be evaluated in mouse intestine epithelial normal and preneoplastic (YAMC and IMCE) cells, as well as mouse hepatic ImHep cells. Combinations that yield most significant results in part A above will be tested in vivo in a normal C57BL mouse model. 2) Evaluate UGT induction as a mechanism for chemoprevention by phytochemical combinations. Whether synergistic UGT induction by phytochemical combinations is a mechanism for enhanced chemoprevention will be evaluated in mice. Combinations with the highest predicted efficacy from Aim 1 will be tested in a dextran sulfate sodium + 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (DSS/PhIP) colon adenocarcinoma mouse model, and aberrant crypt foci (ACF), tumor size/frequency, and ugt induction will be measured. Chemopreventive efficacy will be compared against that of Celecoxib, a known CRC preventive agent. Data from the proposed aims will form the basis of future studies to evaluate additional metabolizing enzymes and transporters that are modulated by phytochemicals. PUBLIC HEALTH RELEVANCE: This project focuses on prevention of colorectal cancer with promising dietary chemicals. The proposed studies will evaluate efficacy of dietary chemical combinations in increasing metabolism and therefore greater detoxification of cancer-causing agents. Preventing colorectal cancer with safe chemicals derived from foods is expected to significantly decrease the burden of this disease.