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01-02-2018

Modulatory Effect of Aerobic Exercise Training on Doxorubicin-Induced Cardiotoxicity in Rats with Different Ages

Authors: Mehdi Ahmadian, Valiollah Dabidi Roshan

Published in: Cardiovascular Toxicology | Issue 1/2018

Abstract

We tested the hypothesis that aerobic exercise training (AET) would modulate doxorubicin-induced cardiotoxicity in rats of various ages. Wistar male rats (n = 72) were assigned to three groups (young, adult, and elderly) with three subgroups for each age: doxorubicin (DG, n = 8), AET + doxorubicin (AETDG, n = 8), AET + Saline (AETSG, n = 8). Following the AET intervention, rats were anesthetized and killed to collect heart tissues in order to determine heat shock protein 70 (HSP70), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-10 (IL10), and c-reactive protein (CRP). Greater levels of SOD and lower levels of MDA were found in young as compared to elderly rats (P < 0.05). CRP was significantly lower in young as compared to adult and elderly rats, respectively (P < 0.05). IL10 also was significantly lower in young as compared to elderly rats (P < 0.05). Furthermore, lower HSP70 and SOD levels were found in DG as compared to AETDG and AETSG (P < 0.05). Conversely, MDA and CRP were significantly higher in DG as compared to other groups (P < 0.05). A significant higher IL10 was noted in DG as compared to AETDG (P < 0.05). Our findings suggest that AET prior to doxorubicin treatment could be useful in minimizing toxicity after chemotherapy with doxorubicin mainly up-regulating of antioxidant defense capacity, with greatest benefit in the young group. Future studies examining the exercise-induced changes and age-related differences following chemotherapy are necessary in human.

Sin, T. K., Tam, B. T., Yung, B. Y., Yip, S. P., Chan, L. W., Wong, C. S., et al. (2015). Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis. The Journal of Physiology, 593, 1887–1899.CrossRefPubMedPubMedCentral

Pecoraro, M., Del Pizzo, M., Marzocco, S., Sorrentino, R., Ciccarelli, M., Iaccarino, G., et al. (2016). Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity. Toxicology and Applied Pharmacology, 293, 44–52.CrossRefPubMed

Zhang, S., Liu, X., Bawa-Khalfe, T., Lu, L.-S., Lyu, Y. L., Liu, L. F., et al. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature Medicine, 18, 1639–1642.CrossRefPubMed

Strait, J. B., & Lakatta, E. G. (2012). Aging-associated cardiovascular changes and their relationship to heart failure. Heart Failure Clinics, 8, 143–164.CrossRefPubMedPubMedCentral

Løhmann, D. J., Abrahamsson, J., Ha, S.-Y., Jónsson, Ó. G., Koskenvuo, M., Lausen, B., et al. (2016). Effect of age and body weight on toxicity and survival in pediatric acute myeloid leukemia: Results from NOPHO-AML 2004. Haematologica haematol. 2016.146175.

Mustian, K. M., Sprod, L. K., Janelsins, M., Peppone, L. J., & Mohile, S. (2012). Exercise recommendations for cancer-related fatigue, cognitive impairment, sleep problems, depression, pain, anxiety, and physical dysfunction: A review. Oncology & Hematology Review, 8, 81.CrossRef

Umanskaya, A., Santulli, G., Xie, W., Andersson, D. C., Reiken, S. R., & Marks, A. R. (2014). Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging. Proceedings of the National Academy of Sciences, 111, 15250–15255.CrossRef

Behnke, B. J., Ramsey, M. W., Stabley, J. N., Dominguez, J. M., Davis, R. T., McCullough, D. J., et al. (2012). Effects of aging and exercise training on skeletal muscle blood flow and resistance artery morphology. Journal of Applied Physiology, 113, 1699–1708.CrossRefPubMedPubMedCentral

Jones, L. W., Habel, L. A., Weltzien, E., Castillo, A., Gupta, D., Kroenke, C. H., et al. (2016). Exercise and risk of cardiovascular events in women with nonmetastatic breast cancer. Journal of Clinical Oncology, 34, 2743–2749.CrossRefPubMedPubMedCentral

10.

Scott, J. M., Lakoski, S., Mackey, J. R., Douglas, P. S., Haykowsky, M. J., & Jones, L. W. (2013). The potential role of aerobic exercise to modulate cardiotoxicity of molecularly targeted cancer therapeutics. The Oncologist, 18, 221–231.CrossRefPubMedPubMedCentral

11.

Lien, C.-Y., Jensen, B. T., Hydock, D. S., & Hayward, R. (2015). Short-term exercise training attenuates acute doxorubicin cardiotoxicity. Journal of Physiology and Biochemistry, 71, 669–678.CrossRefPubMed

12.

Hydock, D. S., Lien, C.-Y., Jensen, B. T., Parry, T. L., Schneider, C. M., & Hayward, R. (2012). Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity. Experimental Biology and Medicine, 237, 1483–1492.CrossRefPubMed

13.

Dolinsky, V. W., Rogan, K. J., Sung, M. M., Zordoky, B. N., Haykowsky, M. J., Young, M. E., et al. (2013). Both aerobic exercise and resveratrol supplementation attenuate doxorubicin-induced cardiac injury in mice. American Journal of Physiology-Endocrinology and Metabolism: ajpendo, 00044, 02013.

14.

Roshan, V. D., Assali, M., Moghaddam, A. H., Hosseinzadeh, M., & Myers, J. (2011). Exercise training and antioxidants effects on rat heart tissue exposed to lead acetate. International Journal of Toxicology, 30, 190–196.CrossRefPubMed

15.

Ascensão, A., Magalhães, J., Soares, J., Ferreira, R., Neuparth, M., Marques, F., et al. (2006). Endurance exercise training attenuates morphological signs of cardiac muscle damage induced by doxorubicin in male mice. Basic and Applied Myology, 16, 27–35.

16.

Desai, V. G., Herman, E. H., Moland, C. L., Branham, W. S., Lewis, S. M., Davis, K. J., et al. (2013). Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F 1 mouse model. Toxicology and Applied Pharmacology, 266, 109–121.CrossRefPubMed

17.

Ichikawa, Y., Ghanefar, M., Bayeva, M., Wu, R., Khechaduri, A., Prasad, S. V. N., et al. (2014). Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. The Journal of Clinical Investigation, 124, 617–630.CrossRefPubMedPubMedCentral

18.

Saad, S. Y., Najjar, T. A., & Alashari, M. (2004). Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration. Journal of Biochemical and Molecular Toxicology, 18, 78–86.CrossRefPubMed

19.

Octavia, Y., Tocchetti, C. G., Gabrielson, K. L., Janssens, S., Crijns, H. J., & Moens, A. L. (2012). Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. Journal of Molecular and Cellular Cardiology, 52, 1213–1225.CrossRefPubMed

20.

Accordino, M. K., Neugut, A. I., & Hershman, D. L. (2014). Cardiac effects of anticancer therapy in the elderly. Journal of Clinical Oncology, 32, 2654–2661.CrossRefPubMedPubMedCentral

21.

Kongsted, P., Svane, I. M., Lindberg, H., & Sengeløv, L. (2016). Predictors of chemotherapy-induced toxicity and treatment outcomes in elderly versus younger patients with metastatic castration-resistant prostate cancer. Clinical Genitourinary Cancer, 14, 559–568.CrossRef

22.

Gupta, A. A., Anderson, J. R., Pappo, A. S., Spunt, S. L., Dasgupta, R., Indelicato, D. J., et al. (2012). Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma. Cancer, 118, 1130–1137.CrossRefPubMed

23.

Wu, J., Xia, S., Kalionis, B., Wan, W., & Sun, T. (2014). The role of oxidative stress and inflammation in cardiovascular aging. BioMed Research International. doi:10.1155/2014/615312.

24.

Petersen, K., & Smith, C. (2016). Ageing-associated oxidative stress and inflammation are alleviated by products from grapes. Oxidative Medicine and Cellular Longevity. doi:10.1155/2016/6236309.PubMedPubMedCentral

25.

Ramesh, T., Yoo, S.-K., Kim, S.-W., Hwang, S.-Y., Sohn, S.-H., Kim, I.-W., et al. (2012). Cordycepin (3′-deoxyadenosine) attenuates age-related oxidative stress and ameliorates antioxidant capacity in rats. Experimental Gerontology, 47, 979–987.CrossRefPubMed

26.

Fumoleau, P., Roche, H., Kerbrat, P., Bonneterre, J., Romestaing, P., Fargeot, P., et al. (2006). Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results. Annals of Oncology, 17, 85–92.CrossRefPubMed

27.

Muss, H. B., Berry, D. A., Cirrincione, C., Budman, D. R., Henderson, I. C., Citron, M. L., et al. (2007). Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: The Cancer and Leukemia Group B Experience. Journal of Clinical Oncology, 25, 3699–3704.CrossRefPubMed

28.

Chicco, A. J., Schneider, C. M., & Hayward, R. (2006). Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. Journal of Cardiovascular Pharmacology, 47, 182–189.CrossRefPubMed

29.

Chicco, A. J., Hydock, D. S., Schneider, C. M., & Hayward, R. (2006). Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. Journal of Applied Physiology, 100, 519–527.CrossRefPubMed

30.

Scott, J. M., Khakoo, A., Mackey, J. R., Haykowsky, M. J., Douglas, P. S., & Jones, L. W. (2011). Modulation of anthracycline-induced cardiotoxicity by aerobic exercise in breast cancer current evidence and underlying mechanisms. Circulation, 124, 642–650.CrossRefPubMedPubMedCentral

31.

Campia, U., & Barac, A. (2016). Exercise and aerobic fitness to reduce cancer-related cardiovascular toxicity. Current Treatment Options in Cardiovascular Medicine, 18, 1–15.CrossRef

32.

Cormie, P., Galvão, D. A., Spry, N., Joseph, D., Chee, R., Taaffe, D. R., et al. (2015). Can supervised exercise prevent treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy: A randomised controlled trial. BJU International, 115, 256–266.CrossRefPubMed

33.

Kapur, G., Windsor, P., & MC COWAN, C. (2010). The effect of aerobic exercise on treatment-related acute toxicity in men receiving radical external beam radiotherapy for localised prostate cancer. European Journal of Cancer Care, 19, 643–647.CrossRefPubMed

34.

Iyalomhe, O., Chen, Y., Allard, J., Ntekim, O., Johnson, S., Bond, V., et al. (2015). A standardized randomized 6-month aerobic exercise-training down-regulated pro-inflammatory genes, but up-regulated anti-inflammatory, neuron survival and axon growth-related genes. Experimental Gerontology, 69, 159–169.CrossRefPubMedPubMedCentral

35.

Roh, H.-T., & So, W.-Y. (2016). The effects of aerobic exercise training on oxidant-antioxidant balance, neurotrophic factor levels, and blood–brain barrier function in obese and non-obese men. Journal of Sport and Health Science. doi:10.1016/j.jshs.2016.07.006.

36.

Dias, D., Bernardes, N., Brito, J., Conti, F., Irigoyen, M. C., & De Angelis, K. (2014). Aerobic exercise training decreased oxidative stress in aged females rats after ovarian hormones deprivation (706.11). The FASEB Journal, 28(706), 711.

37.

Kanter, M., Hamlin, R., Unverferth, D., Davis, H., & Merola, A. (1985). Effect of exercise training on antioxidant enzymes and cardiotoxicity of doxorubicin. Journal of Applied Physiology, 59, 1298–1303.CrossRefPubMed

38.

Gleeson, M., Bishop, N. C., Stensel, D. J., Lindley, M. R., Mastana, S. S., & Nimmo, M. A. (2011). The anti-inflammatory effects of exercise: Mechanisms and implications for the prevention and treatment of disease. Nature Reviews Immunology, 11, 607–615.CrossRefPubMed

39.

Jones, L. W., Eves, N. D., Haykowsky, M., Freedland, S. J., & Mackey, J. R. (2009). Exercise intolerance in cancer and the role of exercise therapy to reverse dysfunction. The Lancet Oncology, 10, 598–605.CrossRefPubMed

40.

Barnes, D. E., & Lindahl, T. (2004). Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annual Review of Genetics, 38, 445–476.CrossRefPubMed

41.

Chanchaeva, E., & Aizman, R. (2012). Age-related changes in blood plasma antioxidant activity in population of the southern Altai. Journal of Evolutionary Biochemistry and Physiology, 48, 152–154.CrossRef

Title: Modulatory Effect of Aerobic Exercise Training on Doxorubicin-Induced Cardiotoxicity in Rats with Different Ages
Authors: Mehdi Ahmadian
Valiollah Dabidi Roshan
Publication date: 01-02-2018
Publisher: Springer US
Published in: Cardiovascular Toxicology / Issue 1/2018
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-017-9411-5

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