Cardiotoxicity of Doxorubicin Treatment and Physical Activity: A Systematic Review

Maia, Tauan Nunes; Araujo, Gustavo Bento Ribeiro de; Teixeira, José Antônio Caldas; Alves, Edmundo de Drummond; Dias, Kátia Pedreira

doi:10.5935/2359-4802.20170004

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International Journal of Cardiovascular Sciences

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Review Articles • Int. J. Cardiovasc. Sci. 30 (1) • Jan-Feb 2017 • https://doi.org/10.5935/2359-4802.20170004 copy

Cardiotoxicity of Doxorubicin Treatment and Physical Activity: A Systematic Review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The present study investigated whether the practice of exercise has a protective effect against cardiac toxicity induced by doxorubicin (DOX). A systematic review of randomized clinical trials evaluating the role of exercise in the control or prevention of DOX-induced cardiotoxicity was performed in MEDLINE and LILACS databases. Studies that did not address the main subject of this review, did not mention physical exercise or DOX, studies that evaluated other types of anthracycline-induced toxicities only (muscle, hepatic and renal toxicity) or other effects of exercise on DOX toxicity (fatigue) were excluded. With respect to the variables related to aerobic exercise prescription, there was no direct relationship between the frequency of exercise and the results of the studies. Also, intensity of exercise was not decisive for preservation of cardiac function, although a more intense exercise was associated with improvements in the antioxidant system, which was not observed in studies on lower intensity exercises. No significant differences in exercise effects were observed when it was performed before, during or after the treatment. Therefore, aerobic exercise may exert a protective effect of cardiac functions when performed before, during or after treatment with DOX. However, the mechanisms of this effect are still unknown.

Keywords:
Exercise; Physical Exertion; Anthracyclines; Doxorubicin; Cardiotoxicity; Review

Authors	Population	Treatment protocol	Exercise	Protective effects identified
Chicco et al.⁹9 Ascensão A, Magalhães J, Soares JM, Ferreira R, Neuparth MJ, Marques F, et al. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces development of cardiac apoptosis. Am J Physiol Heart Circ Physiol. 2005;289(2):H722-31.	Female rats (n=28)	10 µ DOX for 60 min	Voluntary 8 weeks before DOX	Resistance against cardiac dysfunction and oxidative damage, increase in heat shock protein (HSP72)
Ascensão et al.¹⁰10 Chicco AJ, Hydock DS, Schneider CM, Hayward R. Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol (1985). 2006;100(2):519-27.	Male rats (n=40)	20 mg/kg single dose	Treadmill running 60 min/day, 5 days/week, 14 weeks before DOX	Maintenance of homeostasis, increase in mitochondrial defenses and reduced oxidative damage.
Chicco et al.¹¹11 Ascensão A, Magalhães J, Soares J, Ferreira R, Neuparth M, Marques F, et al. Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. Int J Cardiol. 2005;100(3):451-60.	Male rats (n=28)	2,5 mg/kg 3 x / week for 2 weeks (15mg/kg)	Treadmill 60 min/day, 5 days/week, 2 weeks during DOX treatment	Attenuated left ventricular dysfunction and apoptotic signal activation.
Ascensão et al.¹²12 Chicco AJ, Schneider CM, Hayward R. Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. J Cardiovasc Pharmacol. 2006;47(2):182-9.	Male rats (n=44)	20 mg/kg single dose	Swimming 1h/day, 5 days/week for 14 weeks before treatment	Increase in cardiac muscle tolerance to DOX, with increased response of antioxidant system.
Chicco et al.¹³13 Wonders KY, Hydock DS, Schneider CM, Hayward R. Acute exercise protects against doxorubicin cardiotoxicity. Integr Cancer Ther. 2008;7(3):147-54.	Male rats (n=42)	15 mg/kg single dose	Treadmill 1h/day, 5 days/week for 14 weeks before treatment	Attenuated cardiac dysfunction and lipid peroxidation, and increased HSP72.
Wonders et al.¹⁴14 Hydock DS, Lien CY, Schneider CM, Hayward R. Exercise preconditioning protects against doxorubicin-induced cardiac dysfunction. Med Sci Sports Exerc. 2008;40(5):808-17.	Male rats (n=not specified)	15 mg/kg single dose	Treadmill 1 hour on a single day before DOX	Prevented cardiac dysfunction.
Hydock et al.¹⁵15 Kavazis AN, Smuder AJ, Min K, Tümer N, Powers SK. Short-term exercise training protects against doxorubicin-induced cardiac moticondrial damage independent of HSP72. Am J Physiol Heart Circ Physiol. 2010;299(5):H1515-24.	Male rats (n=147)	10 mg/kg single dose	Voluntary and treadmill, 1h/day, 5 days/week for 8 weeks before treatment	Protected against cardiotoxicity for up to 10 days, preserving cardiac function and myosin heavy chain expression.
Wonders et al.¹⁶16 Ascensão A, Lumini-Oliveira J, Machado NG, Ferreira RM, Gonçalves IO, Moreira AC, et al. Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats. Clin Sci (Lond). 2011;120(1):37-49.	Female rats (n=45)	DOX 10mg/kg single dose + GW2974	Treadmill 60 min/day, 5 days/week for 8 weeks before treatment	Preserved cardiac function and decreased apoptosis signaling and lipid peroxidation.
Kavazis et al.¹⁷17 Hydock DS, Lien CY, Jensen BT, Schneider CM, Hayward R. Exercise preconditioning provides long-term protection against early chronic doxorubicin cardiotoxicity. Integr Cancer Ther. 2011;10(1):47-57.	Male rats (n=28)	20 mg/kg single dose	Treadmill 60 min/day, 5 days/week for one week	Attenuated mitochondrial damage and preserved the antioxidant metabolism.
Ascensão et al.¹⁸18 Ashraf J, Roshan VD. Is short-term exercise a therapeutic tool for improvement of cardioprotection against DOX-induced cardiotoxicity? An experimental controlled protocol in rats. Asian Pac J Cancer Prev. 2012;13(8):4025-30.	Male rats (n=20)	20 mg/kg single dose	Treadmill, 1hour on a single day before DOX	Prevented the decrease in mitochondrial function and antioxidant metabolism
Hydock et al.¹⁹19 Shirinbayan V, Roshan VD. Pretreatment effect of running exercise on HSP70 and DOX-induced cardiotoxicity. Asian Pac J Cancer Prev. 2012;13(11):5849-55.	Female rats (n=49)	15 mg/kg single dose + goserelin acetate	Treadmill 60 min/day, for 8 weeks during treatment	Attenuated dysfunction of left ventricle and mitral and aortic valves.
Hydock et al.²⁰20 Martins RA, Minari AL, Chaves MD, Santos RW, Barbisan LF, Ribeiro DA. Exercise preconditioning modulates genotoxicity induced by doxorubicin in multiple organs of rats. Cell Biochem Funct. 2012;30(4):293-6.	Male rats (n=94)	1 mg/kg/day for 10 days (10 mg/kg)	Voluntary and treadmill, 1h/day, 5 days/week for 8 weeks before treatment	Prevented cardiac dysfunction and expression of myosin heavy chain even after 1 month of treatment.
Hornsby et al ²¹21 Smuder AJ, Kavazis AN, Min K, Powers SK. Doxorubicin-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals. J Appl Physiol (1985). 2013;115(2):176-85.	Humans (n=20)	60 mg/m² + 600 mg/m² cyclophosphamide One dose every 3 weeks for 12 weeks.	Cycle ergometry 60 min/day, 3 days/week for 12 weeks during treatment.	Attenuated the increase in natriuretic peptides.
Hayward et al.⁷7 Hayward R, Lyen CY, Jensen BT, Hydock DS, Schneider CM. Exercise training mitigates anthracycline-induced chronic cardiotoxicity in a juvenile rat model. Pediatr Blood Cancer. 2012;59(1):149-54.	Rat pups (n=64)	2 mg/kg/day during 12 days (14 mg/kg)	Voluntary for 10 weeks during and after treatment	Preserved cardiac growth curve and body mass, and attenuated cardiac dysfunction.
Ashrafi and Roshan²²22 Marques-Aleixo I, Santos-Alves E, Mariani D, Rizo-Roca D, Padrão AI, Rocha-Rodrigues S, et al. Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress. Mitochondrion. 2015;20:22-33.	Male rats (n=48)	10 mg/kg, 20 mg/kg	Treadmill warm up + 39 min/day, 5 days/week for 4 weeks before DOX	Protected against oxidative damage and preserved the balance between production and catabolism of oxidative agents oxidative.
Shirinbayan and Roshan ²³23 Chicco AJ, Schneider CM, Hayward R. Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart. Am J Physiol Regul Integr Comp Physiol. 2005;289(2):R424-31.	Male rats (n=48)	10mg/kg, 20mg/kg	Treadmill warm up + 39 min/day, 5 days/week for 4 weeks before DOX	Decrease the risk of cardiac disturbance and preserved the antioxidant systems.
Martins et al.²⁴24 Wonders KY, Hydock DS, Greufe S, Schneider CM, Hayward R. Endurance exercise training preserves cardiac function in rats receiving doxorubicin and the HER-2 inhibitor GW2974. Cancer Chemother Pharmacol. 2009;64(6):1105-13.	Male rats (n=12)	15 mg/kg single dose	Swimming 60 min/day, 5 days/week, for over 21 days of treatment	Protection to cardiac cell DNA.
Smuder et al.²⁵25 Hydock DS, Parry TL, Jensen BT, Lien CY, Schneider CM, Hayward R. Effects of endurance training on combined goserelin acetate and doxorubicin treatment-induced cardiac dysfunction. Cancer Chemother Pharmacol. 2011;68(3):685-92.	Male rats (n=24)	20 mg/kg single dose	Treadmill 60 min/day, 5 days/week for one week before treatment	Inhibited the increase in lysosomal autophagy signaling.
Jensen et al.²⁶26 Jensen BT, Lien CY, Hydock DS, Schneider CM, Hayward R. Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. J Cardiovasc Pharmacol. 2013;62(3):263-9.	Female rats (n=77)	10 mg/kg single dose	Voluntary and treadmill, 1h/day, 5 days/week for 10 weeks before treatment	Reduced the time and the level of myocardial DOX accumulation.
Marques-Aleixo et al.²⁷27 Hornsby WE, Douglas PS, West MJ, Kenjale AA, Lane AR, Schwitzer ER, et al. Safety and efficacy of aerobic training in operable breast cancer patients receiving neoadjuvant chemotherapy: a phase II randomized trial. Acta Oncol. 2014;53(1):65-74.	Male rats (n=36)	2 mg/kg/ week for 7 weeks	Voluntary and treadmill 1 h/day, 5 days/week for 12 weeks	Improved mitochondrial bioenergetic fitness and prevented the damage caused by oxidative stress.

Studies	Cardioprotective mechanisms
Chicco et al.⁹9 Ascensão A, Magalhães J, Soares JM, Ferreira R, Neuparth MJ, Marques F, et al. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces development of cardiac apoptosis. Am J Physiol Heart Circ Physiol. 2005;289(2):H722-31.	Maintenance of internal pressure and attenuation of lipid peroxidation in left ventricle. Increased expression of the heat shock protein HSP7. No significant results in mitochondrial expression of superoxide dismutase (or isoforms) in the heart of trained animals.
Ascensão et al.¹⁰10 Chicco AJ, Hydock DS, Schneider CM, Hayward R. Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol (1985). 2006;100(2):519-27.	Completely prevented the effect of DOX on state-3 respiration, respiratory control ratio, and uncoupled respiration. Decreased DOX-induced increase in calcium sensitivity, increase in mitochondrial protein carbonyl groups, malondialdehyde, Bax, Bax/BCLW ratio, tissue caspase-3 activity. Training also increased the expression of mitochondrial HSP-60 and tissue HSP-70.
Chicco et al.¹¹11 Ascensão A, Magalhães J, Soares J, Ferreira R, Neuparth M, Marques F, et al. Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. Int J Cardiol. 2005;100(3):451-60.	Low-intensity exercise did not provide a sufficiently intense stimulus to change HSP72 and SOD expression. On the other hand, exercise attenuated left ventricular dysfunction and apoptotic signal activation induced by DOX.
Ascensão et al.¹²12 Chicco AJ, Schneider CM, Hayward R. Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. J Cardiovasc Pharmacol. 2006;47(2):182-9.	The levels of oxidative stress markers indicated that exercise decreased acute DOX-induced disturbances. The authors suggested that glutathione and HSP responses may have been essential for the defense against DOX-related free radicals.
Chicco et al.¹³13 Wonders KY, Hydock DS, Schneider CM, Hayward R. Acute exercise protects against doxorubicin cardiotoxicity. Integr Cancer Ther. 2008;7(3):147-54.	Attenuated the decrease in cardiac functions: heart rate, left ventricular developed pressure, left ventricular systolic function, dP/dt max, left ventricular relaxation, minimum DT/DP. Completely prevented DOX-induced MDA+4HAE increase, protecting against lipid peroxidation. No significant changes in SOD or HSP72 in left ventricle.
Wonders et al.¹⁴14 Hydock DS, Lien CY, Schneider CM, Hayward R. Exercise preconditioning protects against doxorubicin-induced cardiac dysfunction. Med Sci Sports Exerc. 2008;40(5):808-17.	Attenuated the decrease in the end-diastolic pressure/left ventricular diastolic pressure ratio and prevented the DOX-induced increase in MDA + 4 HAE, suggesting that exercise reduced left ventricular lipid peroxidation.
Hydock et al.¹⁵15 Kavazis AN, Smuder AJ, Min K, Tümer N, Powers SK. Short-term exercise training protects against doxorubicin-induced cardiac moticondrial damage independent of HSP72. Am J Physiol Heart Circ Physiol. 2010;299(5):H1515-24.	Attenuated DOX-induced a-MHC upregulation
Wonders et al.¹⁶16 Ascensão A, Lumini-Oliveira J, Machado NG, Ferreira RM, Gonçalves IO, Moreira AC, et al. Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats. Clin Sci (Lond). 2011;120(1):37-49.	Preserved cardiac functions, decreased MDA+4-HAE, caspase-3 and caspase-8 levels.
Kavazis et al.¹⁷17 Hydock DS, Lien CY, Jensen BT, Schneider CM, Hayward R. Exercise preconditioning provides long-term protection against early chronic doxorubicin cardiotoxicity. Integr Cancer Ther. 2011;10(1):47-57.	Protected against deleterious effect of DOX on cardiomyocytes, by increasing the expression of antioxidant enzymes and HSP72 in cardiomyocytes. However, a model of HSP72 isolation, tested by the authors, did not eliminate the exercise-induced cardioprotective effect, suggesting that such effect was caused by the increase in antioxidant enzymes.
Ascensão et al.¹⁸18 Ashraf J, Roshan VD. Is short-term exercise a therapeutic tool for improvement of cardioprotection against DOX-induced cardiotoxicity? An experimental controlled protocol in rats. Asian Pac J Cancer Prev. 2012;13(8):4025-30.	Prevented the decease in cardiac mitochondrial functions, preserved mitochondrial phosphorylation capacity, attenuated the decreased tolerance to mitochondrial permeability transition pore opening, protected the activity of cardiac mitochondrial chain complexes I and V, and increased caspase 3 and 9 and mitochondrial SOD activities.
Hydock et al.¹⁹19 Shirinbayan V, Roshan VD. Pretreatment effect of running exercise on HSP70 and DOX-induced cardiotoxicity. Asian Pac J Cancer Prev. 2012;13(11):5849-55.	Prevented a 22% reduction in left ventricular ejection fraction and depressed aortic and mitral valve blood flow. Preserved MHC, but had no effect on sarcoendoplasmic reticulum Ca2+ ATPase 2a expression.
Hydock et al.²⁰20 Martins RA, Minari AL, Chaves MD, Santos RW, Barbisan LF, Ribeiro DA. Exercise preconditioning modulates genotoxicity induced by doxorubicin in multiple organs of rats. Cell Biochem Funct. 2012;30(4):293-6.	Preserved maximal and mean mitral valve blood flow.
Hornsby et al. ²¹21 Smuder AJ, Kavazis AN, Min K, Powers SK. Doxorubicin-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals. J Appl Physiol (1985). 2013;115(2):176-85.	Attenuated the increase in natriuretic peptides.
Hayward et al.⁷7 Hayward R, Lyen CY, Jensen BT, Hydock DS, Schneider CM. Exercise training mitigates anthracycline-induced chronic cardiotoxicity in a juvenile rat model. Pediatr Blood Cancer. 2012;59(1):149-54.	Preserved diastolic and systolic function by preventing the decrease in heart rate, blood flow velocity, and isovolumetric time increase, and decreased the frequency of intrinsic depolarization. There was no significant effect on a- and b-MHC expression.
Ashraf e Roshan²²22 Marques-Aleixo I, Santos-Alves E, Mariani D, Rizo-Roca D, Padrão AI, Rocha-Rodrigues S, et al. Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress. Mitochondrion. 2015;20:22-33.	Increased Apelin and SOD, and decrased MDA.
Shirinbayan e Roshan²³23 Chicco AJ, Schneider CM, Hayward R. Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart. Am J Physiol Regul Integr Comp Physiol. 2005;289(2):R424-31.	Increased HSP72 and SOD, and decreased MDA.
Martins et al. ²⁴24 Wonders KY, Hydock DS, Greufe S, Schneider CM, Hayward R. Endurance exercise training preserves cardiac function in rats receiving doxorubicin and the HER-2 inhibitor GW2974. Cancer Chemother Pharmacol. 2009;64(6):1105-13.	Decreased DNA damage in cardiac cells without a defined mechanism. The authors hypothesized that exercise provided protection against oxidative stress and upregulation of apoptotic pathways.
Smuder et al. ²⁵25 Hydock DS, Parry TL, Jensen BT, Lien CY, Schneider CM, Hayward R. Effects of endurance training on combined goserelin acetate and doxorubicin treatment-induced cardiac dysfunction. Cancer Chemother Pharmacol. 2011;68(3):685-92.	Prevented myofiber ultra-structure damage, inhibited Beclin-1(BCL1) increase and Beclin-2 (BCL-2) decrease, and decreased the BCL1/BCL2 ratio; reduced DOX-induced increase of TAG12, TAG4, TAG7, LC3, Cathepsin-B and Cathepsin-L.
Jensen et al.²⁶26 Jensen BT, Lien CY, Hydock DS, Schneider CM, Hayward R. Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. J Cardiovasc Pharmacol. 2013;62(3):263-9.	Reduced cardiac DOX by unspecified mechanisms.
Marques-Aleixo et al.²⁷27 Hornsby WE, Douglas PS, West MJ, Kenjale AA, Lane AR, Schwitzer ER, et al. Safety and efficacy of aerobic training in operable breast cancer patients receiving neoadjuvant chemotherapy: a phase II randomized trial. Acta Oncol. 2014;53(1):65-74.	Increased the percentage of normal mitochondria and mitochondrial density. Improved state 3 respiration, decreased the delay phase of ADP phosphorylation, enhanced electron transport chain activity at complex I and IV.

Week	Duration	Intensity	Incremental training from the fifth week onwards
	3 sessions of 15-20 min	60% VO₂max.	-
2^nd to 4^th	3 sessions of 30 min	65% VO₂max	-
5^th and 6^th	2 sessions of 30-45 min	60-65% VO₂max	1 session of 20-25 min at ventilator threshold determined by a systematic increase in the VE/VO₂ ratio while VE/VCO₂ remained constant.
7^th to 9^th	2 sessions of 60 min	65-70% VO₂max	1 session of 20-25 min at ventilator threshold determined by a systematic increase in the VE/VO₂ ratio while VE/VCO₂ remained constant.
10^th to 12^th	2 sessions of 60 min	60-70% VO₂max	Interval trainings of 30 seconds at 100% VO₂max, followed by 60 s of active recovery (total of 10-15 cycles).

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