Concomitant low-dose doxorubicin treatment and exercise

Kathleen Sturgeon, Keri Schadler, Geetha Muthukumaran, Dennis Ding, Akinyemi Bajulaiye, Nicholas J. Thomas, Victor Ferrari, Sandra Ryeom, Joseph R. Libonati

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 × 105) were injected subcutaneously into the scruff of 6- to 8-wk-old male C57BL/6 mice (n = 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) + vehicle, 2) SED + DOX, 3) EX + vehicle, and 4) EX + DOX. Tumor volume was attenuated in DOX and lowest in EX + DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, β-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOX-induced cardiotoxicity in a murine model of melanoma.

Original languageEnglish (US)
Pages (from-to)R685-R692
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume307
Issue number6
DOIs
StatePublished - Sep 15 2014

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Doxorubicin
Exercise
Therapeutics
Stroke Volume
Melanoma
Body Weight
Weights and Measures
Neoplasms
Proto-Oncogene Proteins c-akt
Myosin Heavy Chains
Sirolimus
Tumor Burden
Inbred C57BL Mouse
Cardiac Myocytes
Walking
Fibrosis

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

Sturgeon, Kathleen ; Schadler, Keri ; Muthukumaran, Geetha ; Ding, Dennis ; Bajulaiye, Akinyemi ; Thomas, Nicholas J. ; Ferrari, Victor ; Ryeom, Sandra ; Libonati, Joseph R. / Concomitant low-dose doxorubicin treatment and exercise. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2014 ; Vol. 307, No. 6. pp. R685-R692.
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Sturgeon, K, Schadler, K, Muthukumaran, G, Ding, D, Bajulaiye, A, Thomas, NJ, Ferrari, V, Ryeom, S & Libonati, JR 2014, 'Concomitant low-dose doxorubicin treatment and exercise', American Journal of Physiology - Regulatory Integrative and Comparative Physiology, vol. 307, no. 6, pp. R685-R692. https://doi.org/10.1152/ajpregu.00082.2014

Concomitant low-dose doxorubicin treatment and exercise. / Sturgeon, Kathleen; Schadler, Keri; Muthukumaran, Geetha; Ding, Dennis; Bajulaiye, Akinyemi; Thomas, Nicholas J.; Ferrari, Victor; Ryeom, Sandra; Libonati, Joseph R.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 307, No. 6, 15.09.2014, p. R685-R692.

Research output: Contribution to journalArticle

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T1 - Concomitant low-dose doxorubicin treatment and exercise

AU - Sturgeon, Kathleen

AU - Schadler, Keri

AU - Muthukumaran, Geetha

AU - Ding, Dennis

AU - Bajulaiye, Akinyemi

AU - Thomas, Nicholas J.

AU - Ferrari, Victor

AU - Ryeom, Sandra

AU - Libonati, Joseph R.

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N2 - Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 × 105) were injected subcutaneously into the scruff of 6- to 8-wk-old male C57BL/6 mice (n = 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) + vehicle, 2) SED + DOX, 3) EX + vehicle, and 4) EX + DOX. Tumor volume was attenuated in DOX and lowest in EX + DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, β-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOX-induced cardiotoxicity in a murine model of melanoma.

AB - Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 × 105) were injected subcutaneously into the scruff of 6- to 8-wk-old male C57BL/6 mice (n = 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) + vehicle, 2) SED + DOX, 3) EX + vehicle, and 4) EX + DOX. Tumor volume was attenuated in DOX and lowest in EX + DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, β-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOX-induced cardiotoxicity in a murine model of melanoma.

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