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

项目总结 我们已经表明，癌症患者使用植物膳食补充剂(BDS)的比率比非癌症患者高得多。 癌症患者。然而，将BDS与抗癌药物联合使用可能会无意中导致生命危险 不良事件(AES)。Açaí(Eurpe holacea Mart.)是美国使用的前40种植物性药物之一， 癌症患者越来越多地使用açaíBDS来补充他们的传统化疗药物。我们 研究发现，同时使用阿司匹林和抗癌药物会增加血管AEs的风险 57%的不良反应涉及同时使用阿司匹林，包括心血管疾病症状和 严重后果。这一证据支持了理解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的临床前方法来识别与临床相关的 BDS引起的相互作用，并最终改善治疗结果。我们假设：(1)当 在人体内联合给药，AçaíBDS通过药代动力学非动力学途径与口服抗癌药物相互作用 CYP3A4酶(其他CYP亚型)和/或药物转运体，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 为导致不良反应的临床相关药物相互作用创造了可能性。 目标1：确定同时使用açaíbds和bds引起不良反应的机制 口服抗癌药物。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)， 不同的作用机制和新陈代谢建立概念证明。我们将使用açaíberry做到这一点 原料和BDS提取物(及其相关的被动和非被动扩散成分)。目标 1A：研究非CYP3A4药物动力学或药物-转运体相互作用机制。目标1B： 评价相互作用的药效学机制。 目的2：应用基于代谢组学的化学计量学来鉴定产生血管紧张素转换酶的Açaíbds成分。 我们将使用化学计量学来鉴定对抗癌药物阿萨伊负责的阿萨伊化合物 互动。目标2 A。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分析。 目标2B。确定导致AçaíBDS-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、药代动力学等方面拥有互补的专业知识， 化疗、血管药理学和化学计量学，以及学生指导记录。这 项目是为学生动手参与量身定做的，我们的前期工作涉及6名本科生 学生们。该项目将通过以下方式为研究该机制建立一个更可靠和更具预测性的方法 哪些相关的Açaíbds-抗癌药物相互作用在体内发生，并深入了解其机制和 对阿萨伊毒性和不良反应负责的化合物。这些结果与国家的优先事项保持一致 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.