EVALUATING THE PROTECTIVE EFFECTS OF LOVASTATIN AGAINST DOXORUBICIN INDUCED CARDIOTOXICITY IN balb-c MICE
DOI:
https://doi.org/10.55519/JAMC-02-10528Keywords:
Cardiotoxicity; Creatine Kinase MB; Lactate Dehydrogenase; Doxorubicin; Lovastatin.Abstract
Background: Doxorubicin is one of the most commonly used anti-cancer drugs that treat a large number of haematological and solid malignancies. Its usage in dose and duration is nevertheless restricted by dose related organ damage, particularly cardiotoxicity. Lovastatin is a commonly prescribed drug for hypercholesterolemia and possesses remarkable antioxidant potential. Our study was aimed at evaluating and comparing its cardioprotective effect in two pre-treatment schedules against doxorubicin-induced cardiac damage. Methods: In this lab-based randomized controlled experiment, 40 BALB/c mice were randomly grouped into five groups (n=8). Group 1 served as control whereas Group 2 was given doxorubicin intraperitoneally at a dose of 10mg/kg. Group 3 received 10mg/kg of oral lovastatin for five days. Groups 4 and 5 were administered lovastatin for five and ten consecutive days correspondingly and doxorubicin was given on 3rd and 8th experimental days of these groups. Results: Doxorubicin caused a significant rise in cardiac enzymes; Creatine kinase MB (CK-MB) and Lactate Dehydrogenase (LDH) (p-value ≤0.0001) whereas cardiac histological alterations were ranked as moderate. The damage was significantly attenuated by lovastatin in the ten-day study design with a p-value of ≤0.001 for both LDH and CK-MB whereas a slightly less efficient restoration was observed in the five-day design with p-value of ≤0.001 for LDH and 0.012 for CK-MB. Histological preservation in both pre-treatment schedules was in accordance with the biological markers. Conclusion: In doxorubicin-based regimens, pretreatment for at least seven days with an easily available and safe statin can effectively prevent its potentially life-threatening cardiotoxicity.References
Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016;66(4):271–89.
Wenningmann N, Knapp M, Ande A, Vaidya TR, Ait-Oudhia S. Insights into doxorubicin-induced cardiotoxicity: Molecular mechanisms, preventive strategies, and early monitoring. Mol Pharmacol 2019;96(2):219–32.
Meredith AM, Dass CR. Increasing role of the cancer chemotherapeutic doxorubicin in cellular metabolism. J Pharm Pharmacol 2016;68(6):729–41.
Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol 2012;8(4):647–70.
Conway A, McCarthy AL, Lawrence P, Clark RA. The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review. BMC Cancer 2015;15(1):366.
Liesse K, Harris J, Chan M, Schmidt ML, Chiu B. Dexrazoxane significantly reduces anthracycline-induced cardiotoxicity in pediatric solid tumor patients-a systematic review. J Pediatr Hematol Oncol 2018;40(6):417–25.
Proskuriakova E, Jada K, Kakieu Djossi S, Khedr A, Neupane B, et al. Mechanisms and Potential Treatment Options of Heart Failure in Patients With Multiple Myeloma. Cureus 2021;13(6):e15943.
Ahmadi M, Amiri S, Pecic S, Machaj F, Rosik J, Łos MJ, et al. Pleiotropic effects of statins: A focus on cancer. Biochim Biophys Acta Mol Basis Dis 2020;1866(12):165968.
Timm KN, Tyler DJ. The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity. Cardiovasc Drugs Ther 2020;34(2):255–69.
Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017;120(1):229–43.
Rohilla A, Rohilla S, Kumar A, Khan MU, Deep A. Pleiotropic effects of statins: A boulevard to cardioprotection. Arab J Chem 2016;9:S21–7.
Pentz R, Kaun C, Thaler B, Stojkovic S, Lenz M, Krychtiuk KA, et al. Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue. J Cell Mol Med 2018;22(12):6122–33.
Jiang W, Hu JW, He XR, Jin WL, He XY. Statins: a repurposed drug to fight cancer. J Exp Clin Cancer Res 2021;40(1):1–33.
Muscas M, Seo SS, Louros SR, Osterweil EK. A differential effect of lovastatin versus simvastatin in neurodevelopmental disorders. eNeuro 2020;7(4):162–20.
Henninger C, Huelsenbeck J, Huelsenbeck S, Grösch S, Schad A, Lackner KJ, et al. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. Toxicol Appl Pharmacol 2012;261(1):66–73.
Salouege I, Ben Ali R, Ben Saïd D, Elkadri N, Kourda N, Lakhal M, et al. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. J Cancer Res Ther 2014;10(2):274–8.
Zhang S, You ZQ, Yang L, Li LL, Wu YP, Gu LQ, et al. Protective effect of Shenmai injection on doxorubicin-induced cardiotoxicity via regulation of inflammatory mediators. BMC Complement Altern Med 2019;19(1):317.
Pecoraro M, Del Pizzo M, Marzocco S, Sorrentino R, Ciccarelli M, Iaccarino G, et al. Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity. Toxicol Appl Pharmacol 2016;293:44–52.
Alimoradian A, Ansarihadipour H, Changizi-ashtiyani S, Chehrei A, Talebi R. Protective effects of omega - 3, atorvastatin , vitamin E and vitamin C against doxorubicin - induced cardiotoxicity in rats : a comparison study. Physiol Pharmaocol 2018;22(1):63–72.
Alam MF, Khan G, Safhi MM, Alshahrani S, Siddiqui R, Sivagurunathan Moni S, et al. Thymoquinone ameliorates doxorubicin-induced cardiotoxicity in swiss albino mice by modulating oxidative damage and cellular inflammation. Cardiol Res Pract 2018;2018:1483041.
Jones CBA, USDA-APHIS. Animal Welfare Act and Animal Welfare Regulations. 2013.
Sahu BD, Kumar JM, Kuncha M, Borkar RM, Srinivas R, Sistla R. Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice. Life Sci 2016;144:8–18.
Valcovici M, Andrica F, Serban C, Dragan S. Cardiotoxicity of anthracycline therapy: current perspectives. Arch Med Sci 2016;12(2):428–35.
Henninger C, Fritz G. Statins in anthracycline-induced cardiotoxicity : Rac and Rho , and the heartbreakers. Cell Death Dis 2017;8(1):e2564.
Zhang H, Guo J, Cui S, Zhou Y. Taurine Has Potential Protective Effects against the Chronic Cardiotoxicity Induced by Doxorubicin in Mice. Biol Pharm Bull 2021;44(11):1732–7.
Divakaran SA, Krishnan C, Nair K. Amelioration of doxorubicin induced cardiotoxicity in tumor bearing mice by ferulic acid: a mechanistic study at cellular and biochemical level. Int J Tumor Therap 2012;1(2):6–13.
Gava FN, Zacché E, Ortiz EM, Champion T, Bandarra MB, Vasconcelos RO, et al. Doxorubicin induced dilated cardiomyopathy in a rabbit model: An update. Res Vet Sci 2013;94(1):115–21.
Ramanjaneyulu SV, Trivedi PP, Kushwaha S, Vikram A, Jena GB. Protective role of atorvastatin against doxorubicin-induced cardiotoxicity and testicular toxicity in mice. J Physiol Biochem 2013;69(3):513–25.
Henriksen PA. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart 2018;104(12):971–7.
Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med 2020;7:3–5.
Kim SH, Kim KJ, Kim JH, Kwak JH, Song H, Cho JY, et al. Erratum: Comparison of doxorubicin-induced cardiotoxicity in the ICR mice of different sources. Lab Anim Res 2017;33(4):319.
Henninger C, Huelsenbeck S, Wenzel P, Brand M, Huelsenbeck J, Schad A, et al. Chronic heart damage following doxorubicin treatment is alleviated by lovastatin. Pharmacol Res 2014;91:47–56.
Chotenimitkhun R, Agostino RD, Lawrence JA, Hamilton CA, Jordan JH, Vasu S, et al. Chronic Statin Administration May Attenuate Early Anthracycline-Associated Declines in Left Ventricular Ejection Function. Can J Cardiol 2015;31(3):302–7.
Jalali AS. Statins: Promising Protective Shield against Doxorubicin Cardiotoxicity Statins : Promising Protective Shield against Doxorubicin Cardiotoxicity. Studies 2017;34(12):1595–607.
Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of Statin Therapy on the Risk for Incident Heart Failure in Patients With Breast Cancer Receiving Anthracycline Chemotherapy. J Am Coll Cardiol 2012;60(23):2384–90.
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