# Doxorubicin cardiotoxicity and the protective effects of exercise

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $365,434

## Abstract

Doxorubicin (DOX) is an anthracycline antibiotic used in the treatment of a broad spectrum of human cancers,
including acute leukemia, lymphomas, stomach, breast and ovarian cancers. Unfortunately, the clinical use of
this highly efficacious anticancer drug is limited due to the development of cardiotoxicity in patients. Doxorubicin-
induced cardiotoxicity is a debilitating condition that promotes the onset of congestive heart failure, resulting in
reduced quality of life and increased morbidity. While the mechanisms responsible for DOX-induced cardiac
dysfunction are unclear, it is well known that the incidence of cardiac dysfunction greatly correlates to the
concentration of DOX taken up by the heart. DOX accumulates rapidly within cardiac tissue following exposure,
where it preferentially localizes to the mitochondria and promotes free radical production. Elevated free radical
production in the mitochondria can lead to severe damaging events resulting in cell death, and evidence suggests
that prevention of mitochondrial dysfunction is sufficient to attenuate the cardiotoxic effects of DOX. Therefore,
elucidating ways in which the mitochondrial accumulation of DOX can be reduced could result in the development
of a therapeutic approach to mitigate the cardiotoxic effects of DOX. In this regard, we recently discovered that
endurance exercise training prior to DOX treatment is sufficient to reduce the mitochondrial accumulation of DOX
and preserve cardiac function. While the mechanisms responsible for the exercise-induced reduction in the levels
of cardiac mitochondrial DOX are unknown, we hypothesize that activity-induced increases in the expression of
xenobiotic transport proteins are required. Specifically, the ATP-binding cassette (ABC) transporters are a class
of proteins with the capability of facilitating the efflux of chemotherapeutics from the heart. Moreover, four
mitochondria-localized ABC transporters are expressed in the heart (i.e. ABCB6, ABCB7, ABCB8 and ABCB10),
all of which are upregulated with exercise. Therefore, the goal of this proposal is to establish the effects of these
transport proteins in mediating the exercise-induced extrusion of DOX from the heart, and to determine their
therapeutic potential to prevent DOX-induced cardiac dysfunction. We will accomplish this by testing the
following specific aims: Specific Aim 1) will determine if exercise-induced protection against DOX toxicity is
dependent on increased levels of mitochondria-localized ABC transporters; and Specific Aim 2) will determine
if overexpression of mitochondrial ABC transport proteins in the heart is sufficient to reduce cardiac DOX
accumulation and prevent DOX-induced cardiotoxicity.

## Key facts

- **NIH application ID:** 9897610
- **Project number:** 5R01HL144858-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Ashley Smuder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $365,434
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897610

## Citation

> US National Institutes of Health, RePORTER application 9897610, Doxorubicin cardiotoxicity and the protective effects of exercise (5R01HL144858-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897610. Licensed CC0.

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