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.