Prior Exercise Training Improves Hepatotoxicity and Liver Damage Induced by Different Doses of Doxorubicin
Pretreatment of aerobic exercise
DOI:
https://doi.org/10.35516/jmj.v59i1.2749Keywords:
Aerobic ExerciseAbstract
Background and Aims: Doxorubicin (DOX) is known as a powerful drug in the fight against various cancers. However, clinical use of DOX is restricted by its specific cytotoxic side effects such as hepatoxicity and liver cirrhosis. The purpose of this study is to investigate the effects of aerobic exercise in rats prior to receiving various dosages of DOX.
Materials and Methods: Forty-eight Wistar male rats were divided randomly into training (T) and control (C) groups. After 3 weeks, rats in each group were randomly assigned to 6 subgroups: C+saline, C+DOX10 mg/kg, C+DOX20 mg/kg, T+saline, T+DOX10 mg/kg, and T+DOX20 mg/kg. The training program included treadmill running between 25-39 min/day and 15-17 m/min, 5 days/week. Dox was administered in two different dosages (10 and 20 mg/kg) while the saline groups received saline of a comparable volume. Histopathological analysis of the liver tissues and values of nitric oxide (NO), serum aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were determined.
Results: Although DOX10 mg/kg and, especially, DOX20 mg/kg caused liver cirrhosis and imbalance in MDA, NO, SOD, GPx, AST and ALT levels (p<0.05), the oxidative stress induced by DOX was remarkably reduced by aerobic exercise before administering Dox, as compared to the control group. Moreover, significant differences were detected in MDA, AST, and ALT levels between the T+DOX10 mg/kg and T+DOX20 mg/kg.
Conclusions: The findings demonstrated that aerobic exercise can mitigate DOX-induced hepatotoxicity, which could be attributed to modulating the balance in oxidant/antioxidant capacity during aerobic exercise.
References
Hinkley JM, Morton AB, Ichinoseki-Sekine N, et al. Exercise training prevents doxorubicin-induced mitochondrial dysfunction of the liver. Med Sci Sports Exerc. 2019; 51(6): 1106-1115. doi: 10.1249/MSS.0000000000001887.
Smuder AJ. Exercise stimulates beneficial adaptations to diminish doxorubicin-induced cellular toxicity. Am J PhysiolRegulIntegr Comp Physiol. 2019; 317(5): R662-R672. doi: 10.1152/ajpregu.00161.2019.
Pugazhendhi A, Edison TN, Velmurugan BK, et al.
Toxicity of Doxorubicin (Dox) to different experimental organ systems.Life Sci. 2018; 200: 26-30. doi: 10.1016/j.lfs.2018.03.023.
Tranchita E, Murri A, Grazioli E, et al. The Beneficial Role of Physical Exercise on Anthracyclines Induced Cardiotoxicity in Breast Cancer Patients. Cancers (Basel). 2022; 14(9): 2288.doi: 10.3390/cancers14092288.
Zhang QL, Yang JJ, Zhang HS. Carvedilol (CAR) combined with carnosic acid (CAA) attenuates doxorubicin-induced cardiotoxicity by suppressingexcessive oxidative stress, inflammation, apoptosis and autophagy. Biomed Pharmacother. 2019; 109: 71-83. doi: 10.1016/j.biopha.2018.07.037.
Wang F, Chandra J, Kleinerman ES. Exercise intervention decreases acute and late doxorubicin-induced cardiotoxicity. Cancer Med. 2021; 10(21): 7572-7584.doi: 10.1002/cam4.4283.
Marques-Aleixo I, Santos-Alves E, Oliveira PJ, et al. The beneficial role of exercise in mitigating doxorubicin-induced Mitochondrionopathy. BiochimBiophys Acta Rev Cancer. 2018; 1869(2): 189-199. doi: 10.1016/j.bbcan.2018.01.002.
Ashrafi 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.
Akbarinejad V, Fathi R, Shahverdi A, et al. The relationship of mitochondrial membrane potential, reactive oxygen species, adenosine triphosphate content, sperm plasma membrane integrity, and kinematic properties in warmblood stallions. Equine Vet Sci. 2020; 94: 103267.
doi: 10.1016/j.jevs.2020.103267.
Roshan VD, Ranjbar S, Hosseinzadeh M, et al. Left ventricular oxidant and antioxidant markers induced by lifestyle modification in rats exposed to lead acetate. Eur J Sport Sci. 2011; 12(6): 485-90. doi: 10.1080/17461391.2011.573579.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979; 95(2): 351-8.doi: 10.1016/0003-2697(79)90738-3.
Hu C, Zhang X, Zhang N, et al. Osteocrin attenuates inflammation, oxidative stress, apoptosis, and cardiac dysfunction in doxorubicin-induced cardiotoxicity. Clin Transl Med. 2020; 10(3): e124. doi: 10.1002/ctm2.124.
Rawat PS, Jaiswal A, Khurana A, et al. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic
strategies for effective management. Biomed Pharmacother. 2021; 139: 111708. doi: 10.1016/j.biopha.2021.111708.
Valko M, Rhodes CJ, Moncol J, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006; 160(1): 1-40. doi: 10.1016/j.cbi.2005.12.009.
Leung WS, Kuo WW, Ju DT, et al. Protective effects of diallyl trisulfide (DATS) against doxorubicin-induced inflammation and oxidative stress in the brain of rats.Free Radic Biol Med. 2020; 160: 141-148. doi: 10.1016/j.freeradbiomed. 16. Cui, Jingxuan, Yujia Chen, Qiannan Yang, Peng Zhao, Mian Yang, Xiaoqi Wang, Ge Mang et al. Protosappanin A Protects DOX‐Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis‐Dependent Ferroptosis. Adv. Sci. 2024; 2310227.doi: 10.1002/advs.202310227 17. Rawat, Pushkar Singh, Aiswarya Jaiswal, Amit Khurana, Jasvinder Singh Bhatti, and Umashanker Navik. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomedicine & Pharmacotherapy. 2021; 139: 111708.doi: 10.1016/j.biopha.2021.111708
Prasanna PL, Renu K, Gopalakrishnan AV. New molecular and biochemical insights of doxorubicin-induced hepatotoxicity. Life Sci. 2020; 250: 117599. doi: 10.1016/j.lfs.2020.117599. 19. Aljobaily, Nouf, Michael J. Viereckl, David S. Hydock, et al. Creatine alleviates doxorubicin-induced liver damage by inhibiting liver fibrosis, inflammation, oxidative stress, and cellular senescence. Nutrients. 2020; 13(1): 41.doi: 10.3390/nu13010041.
Ma H, Chen S, Xiong H, et al. Astaxanthin from Haematococcuspluvialis ameliorates the chemotherapeutic drug (doxorubicin) induced liver injury through the Keap1/Nrf2/HO-1 pathway in mice. Food Funct. 2020; 11(5): 4659-4671.doi: 10.1039/c9fo02429h.
Ascensão A, Lumini-Oliveira J, Machado NG, 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.
doi: 10.1042/CS20100254.
Friedenreich CM, Stone CR, Cheung WY, et al. Physical activity and mortality in cancer survivors: a systematic review and meta-analysis. JNCI Cancer Spectr. 2019; 4(1): pkz080.
doi: 10.1093/jncics/pkz080.
Wang F, Iskra B, Kleinerman E, et al. Aerobic exercise during early murine doxorubicin exposure mitigates cardiac toxicity. J PediatrHematol Oncol. 2018; 40(3): 208-215. doi: 10.1097/MPH.0000000000001112.
Ascensão A, Magalhães J, Soares J, et al. Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. Int J Cardiol. 2005; 100(3): 451-60.
doi: 10.1016/j.ijcard.2004.11.004.
Kavazis AN, Smuder AJ, Min K, et al. Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72. Am J Physiol Heart Circ Physiol. 2010; 299(5): H1515-24.
doi: 10.1152/ajpheart.00585.2010.
Shirinbayan V, Roshan VD. Pretreatment effect of running exercise on HSP 70 and DOX-induced cardiotoxicity. Asian Pac J Cancer Prev. 2012; 13(11): 5849-55.
doi: 10.7314/apjcp.2012.13.11.5849.
Lima FD, Stamm DN, Della-Pace ID, et al. Swimming training induces liver mitochondrial
adaptations to oxidative stress in rats submitted to repeated exhaustive swimming bouts. PLoS One. 2013; 8(2): e55668. doi: 10.1371/journal.pone.0055668.
Arazi H, Rahmati S, Ghafoori H. The interaction effects of resistance training and sustanon abuse on liver antioxidant activities and serum enzymes in male rats.Interv Med Appl Sci. 2017; 9(3): 178-183.doi: 10.1556/1646.9.2017.29.
Dallak MA, Bin-Jaliah I, Albawardi A, et al. Swim exercise training ameliorates hepatocyte ultrastructural alterations in rats fed on a high fat and sugar diet. UltrastructPathol. 2018; 42(2): 155-161. doi: 10.1080/01913123.2017.1422581.
Shephard RJ, Johnson N. Effects of physical activity upon the liver. Eur J Appl Physiol. 2015; 115(1): 1-46. doi: 10.1007/s00421-014-3031-6.
Teixeira de Lemos E, Oliveira J, Páscoa Pinheiro J, et al. Regular physical exercise as a strategy to improve antioxidant and anti-inflammatory status: benefits in type 2 diabetes mellitus. Oxid Med Cell Longev. 2012; 741545. doi: 10.1155/2012/741545.
Ghasemi, A., Jeddi, S. and Kashfi, K. The laboratory rat: Age and body weight matter. EXCLI J. 2021; 20: 1431–1445. doi: 10.17179/excli2021-4072
Sengupta P. The laboratory rat: relating its age with human's. Int J Prev Med. 2013; 4(6): 624.PMCID: PMC3733029
Hard GC, Johnson KJ, Cohen SM. A comparison of rat chronic progressive nephropathy with human renal disease—implications for human risk assessment. Critical reviews in toxicology. 2009 ; 39(4): 332-46.doi: 10.1080/10408440802368642
