Pretreatment Effects of Regular Aerobic Training on the IGF System and Hepatotoxicity Induced by Doxorubicin in Rats

  • Published : 2013.12.31


Aims: To examine the pretreatment effects of regular aerobic training on the IGF system (IGF-I, IGFBP-3 and IGF/IGFBP) and doxorubicin(DOX) induced hepatotoxicity in rats. Materials and Methods: Forty-eight male rats were divided into groups:(1) control+placebo (2) $control+DOX_{10}mg{\cdot}kg^{-1}$ (3) $control+DOX_{20}mg{\cdot}kg^{-1}$ (4) training+placebo (5) $training+DOX_{10}mg{\cdot}kg^{-1}$ (6) $training+DOX_{20}mg{\cdot}kg^{-1}$. Hepatotoxicity was induced by DOX with dosages of 10 and 20 $mg{\cdot}kg^{-1}$. The rats in groups 4, 5 and 6 performed treadmill running of 25-54 min/day and 15-20 m/min, 5 days/wk for 6 wks. At the end of the aerobic training protocol, rats in the 1 and 4 groups, in the 2 and 5 groups and in the 3 and 6 groups received saline solution, $DOX_{10}mg{\cdot}kg^{-1}$ and $DOX_{20}mg{\cdot}kg^{-1}$, respectively. Results: Administration of $DOX_{20}mg{\cdot}kg^{-1}$ caused a significant increase in IGF-1 and IGF-1/IGFBP-3, an insignificant decrease in IGFBP-3, as compared to the control+placebo group. However, after six weeks of aerobic training and DOX treatment with $10mg{\cdot}kg^{-1}$ and or/ $20mg{\cdot}kg^{-1}$ an insignificant decrease in IGF-1, an insignificant increase in IGFBP-3 and a significant decrease in IGF-1/IGFBP-3 were detected, in comparison to $C+DOX_{10}$ and $C+DOX_{20}$. Conclusions: Hepatotoxicity of doxorubicin is dose-dependent and pretreatment with regular aerobic training may improve DOX-induced hepatotoxicity by up-regulation of IGFBP3.


  1. Aleem E, Elshayeb A, Elhabachi N, et al (2012). Serum IGFBP-3 is a more effective predictor than IGF-1 and IGF-2 for the development of hepatocellular carcinoma in patients with chronic HCV infection. Oncol Lett, 3, 704-12.
  2. Arikawa AY, Kurzer MS, Thomas W, et al (2010). No effect of exercise on insulin-like growth factor (IGF)-1, insulin and glucose in young women participating in a 16-week randomized controlled trial. Cancer Epidemiol Biomarkers Prev, 19, 2987-90.
  3. Ascensao A, Magalhães J, Soares J, et al (2005). Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. Int J Cardiol, 100, 451-60.
  4. Ascensao A, Magalhaes J, Soares J, et al (2006). Endurance exercise training attenuates morphological signs of cardiac muscle damage induced by doxorubicin in male mice. Basic Appl Myol, 16, 27-35.
  5. Ascensão A, Oliveira PJ, Magalhaes J (2012). Exercise as a beneficial adjunct therapy during Doxorubicin treatment—Role of mitochondria in cardioprotection. Int J Cardiol, 156, 4-10.
  6. Cao H, Wang G, Meng L, et al (2012). Association between circulating levels of IGF-1 and IGFBP-3 and lung cancer risk: a meta-analysis. PLoS One, 7, 49884.
  7. 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, 424-43.
  8. Chicco AJ, Hydock DS, Schneider CM, et al (2006), Hayward R. Low-intensity exercise training during doxorubicin treatment protects againstcardiotoxicity, J Appl Physiol, 100, 519-27.
  9. Chicco AJ, Schneider CM, Hayward R(2006). Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. J Cardiovasc Pharmacol, 47, 182-9.
  10. Dabidi Roshan V, Assali M, HajizadehMoghaddamAk, et al (2011). Exercise training and antioxidants: Effects on rat heart tissue exposed to lead acetate. Int J Toxicol, 30, 190-6.
  11. Dragojevic-Simic VM, Dobric SL, Bokonjic DR, et al (2004). Amifostine protection against doxorubicin cardiotoxicity in rats. Anticancer Drugs, 15, 169-78.
  12. Dziegiel P, Surowiak P, Zabel M (2002). Correlation of histopathological and biochemical appraisal of anthracyclininduced myocardium damage. Folia Histochem Cytobiol, 40, 127-8.
  13. Friedenreich CM, Neilson HK, Woolcott CG, et al (2011). Changes in insulin resistance indicators, IGFs, and adipokines in a year-long trial of aerobic exercise in postmenopausal women. Endocr Relat Cancer, 18, 357-69.
  14. Guo YS, Jin GF, Houston CW, et al (1998). Insulin-like growth factor-I promotes multidrug resistance in MCLM colon cancer cells. J Cell Physiol, 175, 141-8.<141::AID-JCP3>3.0.CO;2-O
  15. HHydock DS, Lien CY, Schneider CM, et al (2008). Exercise preconditioning protects against doxorubicin induced cardiac dysfunction. Med Sci Sports Exerc, 40, 808-17.
  16. Ibrahim SS, Barakat MA,Helmy HS (2010). Modulating Effect of Carvedilol on Doxorubicin-Induced Cardiomyopathy and Hepatic Damage. J Am Sci, 6, 20-32.
  17. Kalyanaraman B, Joseph J, Kalivendi S, et al (2002). Doxorubicininduced apoptosis: implications in cardiotoxicity. Mol Cell Biochem, 234, 119-24.
  18. Kavazis AN, Smuder AJ, Min K, et al (2010). Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72. Am J Physiol Heart Circ Physiol, 5, 1515-24.
  19. Kelishomi RB, Ejtemaeemehr S, Tavangar SM et al(2008). Morphine is protective against doxorubicin-induced cardiotoxicity in rat. J Appl Toxicol, 243, 96-100.
  20. King PD, Perry MC (2001). Hepatotoxicity of chemotherapy. Oncologist, 6, 162-76.
  21. Ludke AR, Al-Shudiefat AA, Dhingra S, et al (2009). A concise description of cardioprotective strategies in doxorubicininduced cardiotoxicity. Can J PhysiolPharmacol, 87, 756-63.
  22. Sprod LK, Janelsins MC, Palesh OG, et al (2012). Health-related quality of life and biomarkers in breast cancer survivors participating in tai chi chuan. J Cancer Surviv, 6, 146-54.
  23. Wang G, Zhang J, Liu L et al(2012). Quercetin potentiates doxorubicin mediated antitumor effects against liver cancer throughp53/Bcl-xl. PLoS One, 7, 51764.
  24. Wonders KY, Hydock DS, Greufe S, et al (2009). Endurance exercise training preserves cardiac function in rats receiving doxorubicin and the HER-2 inhibitor GW2974. Cancer Chemother Pharmacol, 64, 1105-13.
  25. Wonders KY, Hydock DS, Schneider CM, et al (2008). Acute exercise protects against doxorubicin cardiotoxicity. Integr Cancer Ther, 7, 147-54.
  26. Xu M, Sheng L, Zhu X, et al (2010). Protective effect of tetrandrine on doxorubicin-induced cardiotoxicity in rats. Tumori, 96, 460-4.
  27. Yen HC, Oberley TD, Vichitbandha S, et al (1996). Clair DK. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Invest, 98, 1253-60.
  28. Zumkeller W (2001). IGFs and IGFBPs: surrogate markers for diagnosis and surveillance of tumour growth? Mol Pathol, 54, 285-8.

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