Cyclophosphamide-and doxorubicin-induced impairment of high affinity choline uptake and spatial memory can be prevented by dietary choline supplementation in breast tumor bearing mice

Sep 21, 2026

AC chemotherapy (Adriamycin and Cytoxan; doxorubicin and cyclophosphamide) is a common breast cancer treatment that can cause long-lasting chemotherapy-related cognitive impairments (CRCIs) lasting over 20 years and reducing quality of life. AC chemotherapy can suppress ovarian function and lower estradiol (E2), which may decrease high-affinity choline uptake (HACU) and acetylcholine availability. The study proposes that choline supplementation preserves cholinergic function during and after chemotherapy.

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CategoryHealthcare

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Pages25

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Introduction

Chemotherapy and CRCIs in breast cancer

Estradiol, CHT1, and high-affinity choline uptake

Abstract

PLOS ONE OPEN ACCESS Citation: Botelho R, Kirstein CL, Philpot RM (2024) Cyclophosphamide-and doxorubicin-induced impairment of high affinity choline uptake and spatial memory can be prevented by dietary choline supplementation in breast tumor bearing mice. PLoS ONE 19(11): e0305365 . [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1371/journal.pone](10.1371/journal.pone).0305365 Editor: Elingarami Sauli, Nelson Mandela African Institute of Science and Technology, UNITED REPUBLIC OF TANZANIA Received: December 21, 2023 Accepted: May 28, 2024 Published: November 21, 2024 Copyright: © 2024 Botelho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. Funding: RP-The National Center for Complementary and Integrative Health-NCCIH 1R21AT009734, [https://www.nccih.nih.gov/grants/](https://www.nccih.nih.gov/grants/)[ ](https://www.nccih.nih.gov/grants/)[funding-opportunities](funding-opportunities), No role in this study was played by the funding party besides funding. RESEARCH ARTICLE Cyclophosphamide-and doxorubicin-induced impairment of high affinity choline uptake and spatial memory can be prevented by dietary choline supplementation in breast tumor bearing mice Robert Botelho1,2 *, Cheryl L. Kirstein3, Rex M. Philpot1 1 Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America, 2 Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America, 3 Department of Psychology, USF College of Arts & Sciences, University of South Florida, Tampa, Florida, United States of America * [rbotelho@usf.edu](rbotelho@usf.edu) Abstract AC chemotherapy (Adriamycin and Cytoxan, i.e. , doxorubicin and cyclophosphamide, respectively), a common treatment for breast cancer, can lead to significant cognitive side effects, known as Chemotherapy-Related Cognitive Impairments (CRCIs) . These cognitive impairments can persist over 20 years and significantly affect the quality of life for cancer patients and survivors. AC chemotherapy is known to impair ovarian function and reduce circulating estradiol (E2), an effect that can decrease high-affinity choline uptake (HACU) and reduce acetylcholine (ACh) availability. Because ACh is involved in attention, learning and memory function we hypothesized that the cognitive deficits observed during and after adjuvant chemotherapy (AC) are associated with compromised high affinity choline uptake (HACU) due to suppressed ovarian function. Increasing available choline has been demonstrated to enhance HACU under conditions of demand for ACh, therefore we propose that choline supplementation can mitigate CRCIs by maintaining cholinergic function throughout and following chemotherapy treatment. Our study demonstrates cognitive deficits in tumorbearing but not non-tumor-bearing mice during and following AC chemotherapy, suggesting that tumors enhance vulnerability to CRCIs. We found that HACU was impaired in tumorbearing mice administered AC chemotherapy and that a choline-enriched diet can mitigate both the reduction of HACU induced by chemotherapy and deficits in spatial memory, suggesting a protective role of dietary choline against disruptions in HACU and cognitive impairment caused by chemotherapy. This underscores the potential use of dietary choline supplementation as a part of chemotherapeutic interventions. PLOS ONE | [https://doi.org/10.1371/journal.pone.0305365](https://doi.org/10.1371/journal.pone.0305365) November 21, 2024 1 / 25 Competing interests: The authors have declared that no comp

FAQs

What cognitive side effect is associated with AC chemotherapy in breast cancer patients?

AC chemotherapy can lead to chemotherapy-related cognitive impairments (CRCIs), which may persist for 20+ years and affect learning and memory functions.

How might AC chemotherapy impair high-affinity choline uptake?

AC chemotherapy can suppress ovarian function and reduce circulating estradiol (E2), which may act as an allosteric modulator of the CHT1 transporter involved in high-affinity choline uptake (HACU).

What intervention does the study evaluate to prevent cognitive deficits?

The study evaluates dietary choline supplementation, showing it can mitigate reductions in HACU and prevent spatial memory deficits in tumor-bearing mice during and after AC chemotherapy.

Sep 21, 2026

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