Unravelling the mechanism of acai BDS-anticancer drug interaction: A preliminary approach

项目摘要 我们已经表明，癌症患者使用植物性膳食补充剂（BDS）的比例比非植物性膳食补充剂高得多。 癌症患者。然而，将BDS与抗癌药物结合使用可能会无意中导致危及生命的 不良事件（AE）。Açaí（Euterpe oleracea Mart.）是美国最常用的40种植物药之一和 癌症患者越来越多地使用acaí BDS来补充其常规化疗剂。我们 研究发现，同时使用巴西莓和抗癌药物与血管AE风险增加相关 并且57%涉及合并使用阿萨伊的AE包括心血管疾病症状， 严重的后果。这一证据支持了理解这种相互作用的机制的必要性。 发生。我们的长期目标是开发一种预测性临床前方法，用于识别临床相关的 BDS引起的相互作用，并最终改善治疗结果。我们假设，（1）当 在人类共同管理，acaí BDS与口服抗癌药物通过药代动力学相互作用， CYP 3A 4酶（其他CYP亚型）和/或药物转运蛋白，如P-糖蛋白和有机- 阴离子转运多肽，或药效学机制，以及，（2）这种相互作用 产生导致AE的临床相关药物相互作用的可能性。 目的1：确定伴随使用açaí BDS引起AE的机制， 口服抗癌药我们选择了2种FDA批准的乳腺癌药物（甲氨蝶呤和他莫昔芬）， 不同的作用机制和代谢，以建立概念验证。我们将使用巴西莓 原材料和BDS浸提液（及其相关的被动和非被动扩散成分）。目的 1A：研究非CYP 3A 4药代动力学或药物-转运蛋白相互作用机制。目标1B： 评价相互作用的药效学机制。 目标2：应用基于代谢组学的化学计量学来鉴定产生AE的açaí BDS成分。 我们将使用化学计量学来识别负责抗癌药物的açaí化合物 互动目标2A。对阿萨伊植物和BDS提取物以及其他选定的阿萨伊样品进行化学计量学分析。 目标2B确定负责acaí BDS-抗癌药物相互作用的化合物。 我们的团队在天然产物研究，代谢，药代动力学， 化学疗法，血管药理学和化学计量学，以及学生指导的记录。这 项目是专为动手的学生参与，我们的初步工作涉及6个本科生 学生该项目将建立一个更可靠和预测性的方法来研究机制， 其中相关的acaí BDS-抗癌药物相互作用发生在体内，并获得深入了解的机制， 导致阿萨伊毒性和AE的化合物。这些成果符合国家的优先事项， 补充和综合健康中心，并将加强我们的天然产品研究计划。

PROJECT SUMMARY We have shown that cancer patients use botanical dietary supplements (BDS) at a much higher rate than non- cancer patients. However, combining BDS with anticancer drugs can inadvertently lead to life-threatening adverse events (AEs). Açaí (Euterpe oleracea Mart.) is among the top 40 botanicals used in the U.S., and cancer patients increasingly use açaí BDS to complement their conventional chemotherapeutic agents. We found that concomitant use of açaí and anticancer drugs was associated with increased risk for vascular AEs and that 57% of AEs involving concomitant use of açaí included symptoms of cardiovascular disorders and serious outcomes. This evidence supports the need to understand the mechanism by which the interaction occurs. Our long-term goals are to develop a predictive preclinical approach for identifying clinically-relevant interactions induced by BDS and, ultimately, to improve treatment outcomes. We hypothesize that, (1) when co-administered in humans, açaí BDS interact with oral anticancer drugs via pharmacokinetic non- CYP3A4 enzymes (other CYP isoforms) and/or drug transporters such as P-glycoprotein and organic- anion-transporting polypeptides, or pharmacodynamic mechanisms, and that, (2) this interaction creates the potential for clinically relevant drug interactions that result in AEs. Aim 1: Determine the mechanisms responsible for AEs caused by concomitant use of açaí BDS and oral anticancer drugs. We selected 2 FDA-approved breast cancer drugs (methotrexate and tamoxifen) with different mechanisms of action and metabolism to establish proof of concept. We will do so using açaí berry raw material and BDS extracts (and their associated passively and non-passively-diffused constituents). Aim 1A: Investigate the non-CYP3A4 pharmacokinetic or drug-transporter interaction mechanisms. Aim 1B: Evaluate the pharmacodynamic mechanism of interaction. Aim 2: Apply metabolomics-based chemometrics to identify açaí BDS constituents that produce AEs. We will use chemometrics to identify açaí compounds responsible for the açaí BDS-anticancer drug interaction. Aim 2A. Chemometric analysis of açaí plant and BDS extracts and other selected açaí samples. Aim 2B. Identify the compounds responsible for the açaí BDS-anticancer drug interactions. Our team has complementary expertise in natural products research, metabolism, pharmacokinetics, chemotherapy, vascular pharmacology, and chemometrics, as well as a record of student mentorship. This project is tailored for hands-on student involvement, and our preliminary work involved 6 undergraduate students. The project will establish a more reliable and predictive approach for studying the mechanism by which relevant açaí BDS-anticancer drug interactions occur in vivo and gain insights into the mechanisms and compounds responsible for açaí toxicity and AEs. These outcomes align with the priorities of the National Center for Complementary and Integrative Health and will strengthen our natural products research program.