Priority Research Papers:

Normal tissue and tumor microenvironment adaptations to aerobic exercise enhance doxorubicin anti-tumor efficacy and ameliorate its cardiotoxicity in retired breeder mice

Zachary R. Wakefield _, Mai Tanaka, Christine Pampo, Sharon Lepler, Lori Rice, Joy Guingab-Cagmat, Timothy J. Garrett and Dietmar W. Siemann

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Oncotarget. 2021; 12:1737-1748. https://doi.org/10.18632/oncotarget.28057

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Zachary R. Wakefield1, Mai Tanaka1, Christine Pampo1, Sharon Lepler1, Lori Rice1, Joy Guingab-Cagmat2, Timothy J. Garrett2 and Dietmar W. Siemann1

1 Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL 32610, USA

2 Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA

Correspondence to:

Zachary R. Wakefield, email: [email protected]

Keywords: aerobic exercise; breast cancer; hypoxia; doxorubicin; cardiotoxicity

Abbreviations: NWR: non-wheel running; EX: exercising; PBS: phosphate-buffered saline; DOXO: doxorubicin

Received: May 26, 2021     Accepted: August 13, 2021     Published: August 31, 2021

Copyright: © 2021 Wakefield et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Aerobic exercise is receiving increased recognition in oncology for its multiple purported benefits. Exercise is known to induce physiologic adaptations that improve patient quality-of-life parameters as well as all-cause mortality. There also is a growing body of evidence that exercise may directly alter the tumor microenvironment to influence tumor growth, metastasis, and response to anticancer therapies. Furthermore, the physiologic adaptations to exercise in normal tissues may protect against treatment-associated toxicity and allow for greater treatment tolerance. However, the exercise prescription required to induce these beneficial tumor-related outcomes remains unclear. This study characterized the aerobic adaptations to voluntary wheel running in normal tissues and the tumor microenvironment. Female, retired breeder BALB/c mice and syngeneic breast adenocarcinoma cells were utilized in primary tumor and metastasis models. Aerobic exercise was found to induce numerous adaptations across various tissues in these mice, although primary tumor growth and metastasis were largely unaffected. However, intratumoral hypoxia and global metabolism were altered in the tumors of exercising hosts relative to non-wheel running controls. Doxorubicin chemotherapy also was found to be more efficacious at delaying tumor growth with adjuvant aerobic exercise. Additionally, doxorubicin-induced cardiac toxicity was ameliorated in exercising hosts relative to non-wheel running controls. Taken together, these data suggest that the normal tissue and tumor microenvironment adaptations to aerobic exercise can improve doxorubicin efficacy while simultaneously limiting its toxicity.

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