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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我们已经证明，癌症患者使用植物性膳食补充剂 (BDS) 的比例远高于非癌症患者。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。不良事件 (AE) 巴西莓 (Euterpe oleracea Mart.) 是美国使用最多的 40 种植物药之一，并且癌症患者越来越多地使用巴西莓 BDS 来补充其传统化疗药物。发现同时使用巴西莓和抗癌药物与血管 AE 风险增加相关 57% 涉及同时使用巴西莓的 AE 包括心血管疾病症状和该证据支持了解相互作用机制的必要性。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相关的情况。 BDS 引起的相互作用，并最终改善治疗结果，（1）当。在人体中共同给药时，阿萨伊 BDS 通过药代动力学非相互作用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- 阴离子转运多肽或药效机制，以及（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可能性。目标 1：确定同时使用阿萨伊 BDS 和阿萨伊 BDS 引起的 AE 的机制我们选择了2种FDA批准的乳腺癌药物（甲氨蝶呤和他莫昔芬），不同的作用和新陈代谢机制来建立概念证明我们将使用巴西莓来做到这一点。原材料和 BDS 提取物（及其相关的被动和非被动扩散成分）。 1A：研究非 CYP3A4 药代动力学或药物转运蛋白相互作用机制目标 1B：评估相互作用的药效机制。目标 2：应用基于代谢组学的化学计量学来识别产生 AE 的巴西莓 BDS 成分。我们将使用化学计量学来鉴定巴西莓 BDS 抗癌药物中的巴西莓化合物目标 2A。对巴西莓植物和 BDS 提取物以及其他选定的巴西莓样品进行化学计量分析。目标 2B。确定巴西莓 BDS 与抗癌药物相互作用的负责化合物。我们的团队在天然产物研究、代谢、药代动力学、化疗、血管药理学和化学计量学，以及学生指导记录。该项目专为学生参与实践而设计，我们的前期工作涉及 6 名本科生该项目将建立一种更可靠和更具预测性的方法来研究该机制。相关的阿萨伊 BDS 抗癌药物相互作用发生在体内，并深入了解其机制和这些结果与国家的优先事项一致。补充和综合健康中心并将加强我们的天然产品研究计划。