Abstract
Purpose
To determine if endurance exercise training performed prior to administration of the anticancer drugs DOX and GW2974 would be cardioprotective.
Methods
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.
Results
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.
Conclusions
Exercise training protected against the cardiac dysfunction associated with DOX/GW2974 administration and may be related to an inhibition in apoptotic signaling.
Similar content being viewed by others
References
Agarwal A, Said TM (2005) Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int 95:503–507
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 45:1188–1193
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 30:243–254
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 100:451–460
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–H731
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 58:2825–2831
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 25:2510–2518
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–R431
Chicco AJ, Schneider CM, Hayward R (2006) Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. J Cardiovasc Pharmacol 47:182–189
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 8:459–465
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 135:1707–1714
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 30:128–139
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 23:7820–7826
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 1741:173–182
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 1043:151–157
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 48:253–261
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 247:37–44
Hydock DS, Lien CY, Schneider CM, Hayward R (2008) Exercise preconditioning protects against doxorubicin-induced cardiac dysfunction. Med Sci Sports Exerc 40:808–817
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–H3002
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 354:809–820
Kalyanaraman B, Joseph J, Kalivendi S, Wang S, Konorev E, Kotamraju S (2002) Doxorubicin-induced apoptosis: implications in cardiotoxicity. Mol Cell Biochem 234–235:119–124
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 25:2114–2121
Kumar D, Kirshenbaum LA, Li T, Danelisen I, Singal PK (2001) Apoptosis in adriamycin cardiomyopathy and its modulation by probucol. Antioxid Redox Signal 3:135–145
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 279:51141–51147
Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378:394–398
Lee V, Randhawa AK, Singal PK (1991) Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals. Am J Physiol 261:H989–H995
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–H666
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229
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 99:8880–8885
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 92:1991–1998
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 16:2659–2671
Perez EA, Rodeheffer R (2004) Clinical cardiac tolerability of trastuzumab. J Clin Oncol 22:322–329
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 26:1231–1238
Phaneuf S, Leeuwenburgh C (2001) Apoptosis and exercise. Med Sci Sports Exerc 33:393–396
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 353:1659–1672
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 25:3808–3815
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–H2098
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–R1477
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 354:2103–2111
Pugatsch T, Abedat S, Lotan C, Beeri R (2006) Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways. Breast Cancer Res 8:R35
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 40:416–425
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 353:1673–1684
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 61:7196–7203
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 20:1215–1221
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 11:1936–1942
Siu PM, Bryner RW, Martyn JK, Alway SE (2004) Apoptotic adaptations from exercise training in skeletal and cardiac muscles. Faseb J 18:1150–1152
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 344:783–792
Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97:2869–2879
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 23:7811–7819
Taylor RP, Ciccolo JT, Starnes JW (2003) Effect of exercise training on the ability of the rat heart to tolerate hydrogen peroxide. Cardiovasc Res 58:575–581
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 95:45–53
Acknowledgments
This work was supported by the American Cancer Society (RSG-04-259-01-CCE) and the UNC Sponsored Programs and Academic Research Center to RH.
Conflict of interest statement
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wonders, K.Y., Hydock, D.S., Greufe, S. et al. Endurance exercise training preserves cardiac function in rats receiving doxorubicin and the HER-2 inhibitor GW2974. Cancer Chemother Pharmacol 64, 1105–1113 (2009). https://doi.org/10.1007/s00280-009-0967-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-009-0967-z