# Doxorubicin cardiotoxicity and the protective effects of exercise

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $39,778

## Abstract

PROJECT SUMMARY
Doxorubicin (DOX) is a highly effective anticancer anthracycline used in the treatment of a wide variety of solid
tumor malignancies. However, clinical use of this powerful chemotherapeutic is limited by the prevalence of
irreversible cardiac tissue damage, which carries a poor prognosis and is often fatal. While efforts have been
made to identify risk factors, develop less-toxic derivatives and detect subclinical toxicity earlier, there is currently
no consensus on the best approach to prevent anthracycline-induced cardiomyopathy. Thus, further advances
in the understanding of the molecular basis of DOX-induced pathology are needed to generate preventative
strategies. DOX accumulates rapidly within cardiac tissue following exposure, where it preferentially localizes to
the mitochondria and promotes free radical production through redox cycling with NADH dehydrogenase and
iron cycling between Fe2+ and Fe3+. 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 changes in the expression of xenobiotic transport proteins and/or
changes in vascular tight junction integrity may play a role in mediating the entry of DOX into the cardiomyocytes.
Therefore, the goal of this proposal is to establish the effects of exercise training on the expression of solute
carrier transport proteins and on vascular permeability, and to determine if targeting these mechanisms has
therapeutic potential to prevent DOX-induced cardiac dysfunction. We will accomplish this by testing the
following specific aims: Specific Aim 1) will determine the effects of exercise and doxorubicin on the expression
of solute carrier proteins in the heart; and Specific Aim 2) will determine if exercise-induced protection against
DOX cardiotoxicity is related to changes in endothelial function and tight junction permeability.

## Key facts

- **NIH application ID:** 10166985
- **Project number:** 3R01HL144858-03S1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Ashley Smuder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,778
- **Award type:** 3
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166985

## Citation

> US National Institutes of Health, RePORTER application 10166985, Doxorubicin cardiotoxicity and the protective effects of exercise (3R01HL144858-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10166985. Licensed CC0.

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