# Doxorubicin-induced respiratory dysfunction and the protective effects of exercise

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $374,408

## 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 respiratory and diaphragm muscle
dysfunction in patients. Doxorubicin-induced ventilatory impairment is a debilitating condition that promotes the
onset dyspnea, fatigue and exercise intolerance. While the mechanisms responsible for DOX-induced respiratory
insufficiency are unclear, previous work demonstrates that the incidence of ventilatory dysfunction greatly
correlates to the concentration of DOX taken up by the diaphragm. DOX accumulates rapidly within the
diaphragm muscle 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 toxic effects of DOX on the diaphragm. 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
myotoxic 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 diaphragm and ventilatory
function. While the mechanisms responsible for the exercise-induced reduction in the levels of diaphragm
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 diaphragm. Moreover, four
mitochondria-localized ABC transporters are expressed in the diaphragm (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 diaphragm, and
to determine their therapeutic potential to prevent DOX-induced respiratory dysfunction. We will accomplish this
by testing the following specific aims: Specific Aim 1) will determine if exercise-mediated protection against
DOX-induced respiratory dysfunction is dependent on increased levels of mitochondria-localized ABC transport
proteins; and Specific Aim 2) will determine if overexpression of mitochondrial ABC transport proteins in the
diaphragm is sufficient to reduce DOX accumulation and prevent DOX-induced respiratory dysfunction.

## Key facts

- **NIH application ID:** 10150893
- **Project number:** 5R01HL146443-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Ashley Smuder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,408
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150893

## Citation

> US National Institutes of Health, RePORTER application 10150893, Doxorubicin-induced respiratory dysfunction and the protective effects of exercise (5R01HL146443-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10150893. Licensed CC0.

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