Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 6, pp 1105–1113

Endurance exercise training preserves cardiac function in rats receiving doxorubicin and the HER-2 inhibitor GW2974

  • Karen Y. Wonders
  • David S. Hydock
  • Stephanie Greufe
  • Carole M. Schneider
  • Reid Hayward
Original Article



To determine if endurance exercise training performed prior to administration of the anticancer drugs DOX and GW2974 would be cardioprotective.


Rats remained sedentary or exercise trained for 10 weeks. Following the exercise or sedentary period, rats were randomly assigned to treatment groups. Rats in sedentary and exercise groups received saline or a combination of 10 mg/kg DOX and 30 mg/kg GW2974. Cardiac function was assessed 2, 5, or 10 days following treatments.


Sedentary animals receiving DOX/GW2974 experienced significant cardiac dysfunction. At 2-, 5-, and 10-days post, cardiac function in trained, drug-treated animals was significantly preserved. Additionally, animals exercised prior to DOX/GW2974 injections had significantly lower levels of myocardial lipid peroxidation and caspase-3 and -8 activities compared to their sedentary counterparts.


Exercise training protected against the cardiac dysfunction associated with DOX/GW2974 administration and may be related to an inhibition in apoptotic signaling.


Anthracyclines Cardiotoxicity Caspase Heart Physical activity 


  1. 1.
    Agarwal A, Said TM (2005) Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int 95:503–507PubMedCrossRefGoogle Scholar
  2. 2.
    Akishita M, Nagai K, Xi H, Yu W, Sudoh N, Watanabe T, Ohara-Imaizumi M, Nagamatsu S, Kozaki K, Horiuchi M, Toba K (2005) Renin-angiotensin system modulates oxidative stress-induced endothelial cell apoptosis in rats. Hypertension 45:1188–1193PubMedCrossRefGoogle Scholar
  3. 3.
    Arai M, Tomaru K, Takizawa T, Sekiguchi K, Yokoyama T, Suzuki T, Nagai R (1998) Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits. J Mol Cell Cardiol 30:243–254PubMedCrossRefGoogle Scholar
  4. 4.
    Ascensao A, Magalhaes J, Soares J, Ferreira R, Neuparth M, Marques F, Oliveira J, Duarte J (2005) Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. Int J Cardiol 100:451–460PubMedCrossRefGoogle Scholar
  5. 5.
    Ascensao A, Magalhaes J, Soares JM, Ferreira R, Neuparth MJ, Marques F, Oliveira PJ, Duarte JA (2005) Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. Am J Physiol Heart Circ Physiol 289:H722–H731PubMedCrossRefGoogle Scholar
  6. 6.
    Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J (1998) Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58:2825–2831PubMedGoogle Scholar
  7. 7.
    Brown DA, Jew KN, Sparagna GC, Musch TI, Moore RL (2003) Exercise training preserves coronary flow and reduces infarct size following ischemia-reperfusion in rat heart. J Appl Physiol 25:2510–2518Google Scholar
  8. 8.
    Chicco AJ, Schneider CM, Hayward R (2005) Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart. Am J Physiol Regul Integr Comp Physiol 289:R424–R431PubMedGoogle Scholar
  9. 9.
    Chicco AJ, Schneider CM, Hayward R (2006) Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. J Cardiovasc Pharmacol 47:182–189PubMedCrossRefGoogle Scholar
  10. 10.
    Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459–465PubMedCrossRefGoogle Scholar
  11. 11.
    de Beer EL, Bottone AE, van Rijk MC, van der Velden J, Voest EE (2002) Dexrazoxane pre-treatment protects skinned rat cardiac trabeculae against delayed doxorubicin-induced impairment of crossbridge kinetics. Br J Pharmacol 135:1707–1714PubMedCrossRefGoogle Scholar
  12. 12.
    Ehrlich GD, Davey FR, Kirshner JJ, Sninsky JJ, Kwok S, Slamon DJ, Kalish R, Poiesz BJ (1989) A polyclonal CD4+ and CD8+ lymphocytosis in a patient doubly infected with HTLV-I and HIV-1: a clinical and molecular analysis. Am J Hematol 30:128–139PubMedCrossRefGoogle Scholar
  13. 13.
    Ewer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, Valero V, Lenihan DJ (2005) Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 23:7820–7826PubMedCrossRefGoogle Scholar
  14. 14.
    Fiorillo C, Nediani C, Ponziani V, Giannini L, Celli A, Nassi N, Formigli L, Perna AM, Nassi P (2005) Cardiac volume overload rapidly induces oxidative stress-mediated myocyte apoptosis and hypertrophy. Biochim Biophys Acta 1741:173–182PubMedGoogle Scholar
  15. 15.
    Fukunaga M, Miyata S, Higo S, Hamada Y, Ueyama S, Kasuga M (2005) Methylglyoxal induces apoptosis through oxidative stress-mediated activation of p38 mitogen-activated protein kinase in rat Schwann cells. Ann NY Acad Sci 1043:151–157PubMedCrossRefGoogle Scholar
  16. 16.
    Husain K (2003) Interaction of physical training and chronic nitroglycerin treatment on blood pressure, nitric oxide, and oxidants/antioxidants in the rat heart. Pharmacol Res 48:253–261PubMedCrossRefGoogle Scholar
  17. 17.
    Husain K, Somani SM, Boley TM, Hazelrigg SR (2003) Interaction of physical training and chronic nitroglycerin treatment on blood pressure and plasma oxidant/antioxidant systems in rats. Mol Cell Biochem 247:37–44PubMedCrossRefGoogle Scholar
  18. 18.
    Hydock DS, Lien CY, Schneider CM, Hayward R (2008) Exercise preconditioning protects against doxorubicin-induced cardiac dysfunction. Med Sci Sports Exerc 40:808–817PubMedCrossRefGoogle Scholar
  19. 19.
    Jin H, Yang R, Li W, Lu H, Ryan AM, Ogasawara AK, Van Peborgh J, Paoni NF (2000) Effects of exercise training on cardiac function, gene expression, and apoptosis in rats. Am J Physiol Heart Circ Physiol 279:H2994–H3002PubMedGoogle Scholar
  20. 20.
    Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkio S, Flander M, Helle L, Ingalsuo S, Johansson K, Jaaskelainen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820PubMedCrossRefGoogle Scholar
  21. 21.
    Kalyanaraman B, Joseph J, Kalivendi S, Wang S, Konorev E, Kotamraju S (2002) Doxorubicin-induced apoptosis: implications in cardiotoxicity. Mol Cell Biochem 234–235:119–124PubMedCrossRefGoogle Scholar
  22. 22.
    Kobayashi N, Delano FA, Schmid-Schonbein GW (2005) Oxidative stress promotes endothelial cell apoptosis and loss of microvessels in the spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 25:2114–2121PubMedCrossRefGoogle Scholar
  23. 23.
    Kumar D, Kirshenbaum LA, Li T, Danelisen I, Singal PK (2001) Apoptosis in adriamycin cardiomyopathy and its modulation by probucol. Antioxid Redox Signal 3:135–145PubMedCrossRefGoogle Scholar
  24. 24.
    Kuramochi Y, Cote GM, Guo X, Lebrasseur NK, Cui L, Liao R, Sawyer DB (2004) Cardiac endothelial cells regulate reactive oxygen species-induced cardiomyocyte apoptosis through neuregulin-1beta/erbB4 signaling. J Biol Chem 279:51141–51147PubMedCrossRefGoogle Scholar
  25. 25.
    Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398PubMedCrossRefGoogle Scholar
  26. 26.
    Lee V, Randhawa AK, Singal PK (1991) Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals. Am J Physiol 261:H989–H995PubMedGoogle Scholar
  27. 27.
    Liu FF, Stone JR, Schuldt AJ, Okoshi K, Okoshi MP, Nakayama M, Ho KK, Manning WJ, Marchionni MA, Lorell BH, Morgan JP, Yan X (2005) Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. Am J Physiol Heart Circ Physiol 289:H660–H666PubMedCrossRefGoogle Scholar
  28. 28.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRefGoogle Scholar
  29. 29.
    Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, Chien KR, Birchmeier C, Garratt AN (2002) Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci USA 99:8880–8885PubMedCrossRefGoogle Scholar
  30. 30.
    Paik S, Bryant J, Tan-Chiu E, Yothers G, Park C, Wickerham DL, Wolmark N (2000) HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92:1991–1998PubMedCrossRefGoogle Scholar
  31. 31.
    Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ (1998) Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16:2659–2671PubMedGoogle Scholar
  32. 32.
    Perez EA, Rodeheffer R (2004) Clinical cardiac tolerability of trastuzumab. J Clin Oncol 22:322–329PubMedCrossRefGoogle Scholar
  33. 33.
    Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA, Martino S, Gralow JR, Dakhil SR, Ingle JN, Winer EP, Gelmon KA, Gersh BJ, Jaffe AS, Rodeheffer RJ (2008) Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 26:1231–1238PubMedCrossRefGoogle Scholar
  34. 34.
    Phaneuf S, Leeuwenburgh C (2001) Apoptosis and exercise. Med Sci Sports Exerc 33:393–396PubMedCrossRefGoogle Scholar
  35. 35.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRefGoogle Scholar
  36. 36.
    Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH (2007) Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 25:3808–3815PubMedCrossRefGoogle Scholar
  37. 37.
    Powers SK, Criswell D, Lawler J, Martin D, Lieu FK, Ji LL, Herb RA (1993) Rigorous exercise training increases superoxide dismutase activity in ventricular myocardium. Am J Physiol 265:H2094–H2098PubMedGoogle Scholar
  38. 38.
    Powers SK, Demirel HA, Vincent HK, Coombes JS, Naito H, Hamilton KL, Shanely RA, Jessup J (1998) Exercise training improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. Am J Physiol 275:R1468–R1477PubMedGoogle Scholar
  39. 39.
    Pritchard KI, Shepherd LE, O’Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354:2103–2111PubMedCrossRefGoogle Scholar
  40. 40.
    Pugatsch T, Abedat S, Lotan C, Beeri R (2006) Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways. Breast Cancer Res 8:R35PubMedCrossRefGoogle Scholar
  41. 41.
    Quindry J, French J, Hamilton K, Lee Y, Mehta JL, Powers S (2005) Exercise training provides cardioprotection against ischemia-reperfusion induced apoptosis in young and old animals. Exp Gerontol 40:416–425PubMedCrossRefGoogle Scholar
  42. 42.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRefGoogle Scholar
  43. 43.
    Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip SB, Carter MC, Shaw RJ, Jowett A, Stables J, Topley P, Wood ER, Brignola PS, Kadwell SH, Reep BR, Mullin RJ, Alligood KJ, Keith BR, Crosby RM, Murray DM, Knight WB, Gilmer TM, Lackey K (2001) The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res 61:7196–7203PubMedGoogle Scholar
  44. 44.
    Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215–1221PubMedCrossRefGoogle Scholar
  45. 45.
    Seshadri R, Firgaira FA, Horsfall DJ, McCaul K, Setlur V, Kitchen P (1993) Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group. J Clin Oncol 11:1936–1942PubMedGoogle Scholar
  46. 46.
    Siu PM, Bryner RW, Martyn JK, Alway SE (2004) Apoptotic adaptations from exercise training in skeletal and cardiac muscles. Faseb J 18:1150–1152PubMedGoogle Scholar
  47. 47.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  48. 48.
    Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97:2869–2879PubMedCrossRefGoogle Scholar
  49. 49.
    Tan-Chiu E, Yothers G, Romond E, Geyer CE Jr, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811–7819PubMedCrossRefGoogle Scholar
  50. 50.
    Taylor RP, Ciccolo JT, Starnes JW (2003) Effect of exercise training on the ability of the rat heart to tolerate hydrogen peroxide. Cardiovasc Res 58:575–581PubMedCrossRefGoogle Scholar
  51. 51.
    Venturini M, Bighin C, Monfardini S, Cappuzzo F, Olmeo N, Durando A, Puglisi F, Nicoletto O, Lambiase A, Del Mastro L (2006) Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 95:45–53PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Karen Y. Wonders
    • 1
  • David S. Hydock
    • 2
  • Stephanie Greufe
    • 2
  • Carole M. Schneider
    • 2
  • Reid Hayward
    • 2
  1. 1.Department of Health, Physical Education, and RecreationWright State UniversityDaytonUSA
  2. 2.School of Sport and Exercise Science and the Rocky Mountain Cancer Rehabilitation InstituteUniversity of Northern ColoradoGreeleyUSA

Personalised recommendations