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.

Project Narrative Little is known about the combined use of açaí botanical dietary supplements and anticancer drugs among cancer patients and the potential resulting adverse events. The current project will establish a foundation for studying interactions between açaí botanical dietary supplements and anticancer drugs through interdisciplinary studies that are in alignment with the National Center for Complementary and Integrative Health’s interests in quality, efficacy, and safety of dietary supplements. Findings will be used to promote appropriate use of botanical dietary supplements and to improve our understanding of potential adverse events.