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

揭示巴西莓 BDS 与抗癌药物相互作用的机制：初步方法

• 批准号: 10291596
• 负责人: Angela Isabel Calderon
• 金额: $ 44.06万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291596
• 关键词: ABCB1 gene; Adverse event; Affect; Antineoplastic Agents; Attenuated; Automobile Driving; Berry; Biological Assay; Blood Vessels; Botanical dietary supplements; Botanicals; Breast Cancer Cell; CYP2C9 gene; CYP2E1 gene; Cancer Patient; Cardiovascular Diseases; Carrier Proteins; Catechin; Cessation of life; Chemicals; Chemoprotective Agent; Clinical; Complement; Complementary Health; Cytochrome P450; Dangerousness; Data; Data Reporting; Diffuse; Diffusion; Drug Interactions; Drug Kinetics; Drug Transport; Enzyme Inhibitor Drugs; Enzymes; Euterpe; FDA approved; Food Safety; Foundations; Glucosides; Goals; Hospitalization; Human; Impairment; Integrative Medicine; Interdisciplinary Study; Intervention; Intestinal Absorption; Intestines; Lead; Life; Liver; Malignant Neoplasms; Mediating; Mentorship; Metabolic; Metabolism; Methotrexate; Natural Products; OATP Transporters; Oral; Organ; Outcome; Overdose; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Plants; Protein Isoforms; Quercetin; Reporting; Research; Risk; Rodent Model; Safety; Sales; Sampling; Signal Transduction; Standardization; Structure; Students; Symptoms; System; Tamoxifen; Techniques; Testing; Toxic effect; Treatment Failure; Treatment outcome; United States Food and Drug Administration; Vascular Endothelial Cell; Work; base; cancer type; chemical fingerprinting; chemical standardization; chemotherapeutic agent; chemotherapy; clinically relevant; clinically significant; dietary supplements; drug efficacy; experience; improved; in vivo; inhibitor/antagonist; insight; interest; malignant breast neoplasm; metabolomics; nutrition; pre-clinical; prevent; programs; response; undergraduate student

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.

项目摘要 我们已经表明，癌症患者使用植物饮食补充剂（BDS）的速度要比非非 - 癌症患者。但是，将BD与抗癌药结合在一起可能会无意中导致威胁生命 不良事件（AES）。 Açaí（Euterpe Oleracea Mart。）是美国使用的前40名植物之一， 癌症患者使用BDS的增加来完成其常规化学治疗剂。我们 发现同时使用Açaí和抗癌药与血管AES的风险增加有关 57％的AE涉及伴随Açaí的使用包括心血管疾病的症状和 严重的结果。该证据支持了解相互作用的机制 发生。我们的长期目标是开发一种预测性临床前方法来识别临床上的相关性 BDS引起的相互作用，最终是为了改善治疗结果。我们假设这是（1） BDS在人类中共同管理，通过药代动力学非 - 与口服抗癌药物相互作用 CYP3A4酶（其他CYP同工型）和/或药物转运蛋白，例如P-糖蛋白和有机物 - 阴离子传输多肽或药效学机制，（2）这种相互作用 创造了导致AE的临床相关药物相互作用的潜力。 目标1：确定由AçaíBDS伴随使用的AE的机制和 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） 不同的作用和代谢机制以建立概念证明。我们将使用AçaíBerry这样做 原材料和BDS提取物（及其相关的被动和非质量扩散的构成）。目的 1A：研究非CYP3A4药代动力学或药物转运蛋白的相互作用机制。 AIM 1B： 评估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以识别产生AE的BDS构成。 我们将使用化学计量学来识别负责AçaíBDS-Amentancer药物的Açaí化合物 相互作用。目标2a。 Açaí植物和BDS提取物以及其他选定的Açaí样品的化学计量分析。 目标2B。识别负责AçaíBDS-Antimancer药物相互作用的化合物。 我们的团队在天然产品研究，代谢，药代动力学，具有完整的专业知识， 化学疗法，血管药理学和化学计量学以及学生心态的记录。这 项目是针对动手的学生参与量身定制的，我们的初步工作涉及6本大学 学生。该项目将建立一种更可靠和预测的方法来研究该机制 在体内发生哪些相关的BDS-通心药相互作用，并获得了对机制的见解和 负责Açaí毒性和AES的化合物。这些结果与国家的优先事项 互补和综合健康中心，将加强我们的天然产品研究计划。