Protective Role of Silymarin in Early Doxorubicin-induced Cardiac Dysfunction in Children with Acute Lymphoblastic Leukemia

Author(s): Adel A. Hagag*, Walid A. El Shehaby, Aml I. El-Abasy, Maaly M. Mabrouk

Journal Name: Infectious Disorders - Drug Targets
Formerly Current Drug Targets - Infectious Disorders

Volume 19 , Issue 2 , 2019

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Background: Doxorubicin is a well-established chemotherapeutic agent for the treatment of childhood acute lymphoblastic leukemia (ALL), but its efficacy is often limited by its related cardiotoxicity. Protection against doxorubicin-induced cardiotoxicity can be of great value, especially for children. Silymarin has a potent antioxidant property that can be helpful in preventing cardio-toxicity.

Objective: ‘To assess the possible protective role of silymarin against early doxorubicin-induced cardiotoxicity in children with ALL’.

Subjects and Methods: This study was conducted on 80 children with ALL, including 40 patients under doxorubicin therapy and silymarin 420 mg/day for one week after each doxorubicin dose starting from the day of doxorubicin infusion (Group I) and 40 patients under doxorubicin therapy and placebo (Group II). ‘Conventional echo-Doppler measures of left ventricular systolic and diastolic functions and pulsed wave tissue Doppler of lateral mitral annulus were done for all patients’.

Results: After doxorubicin therapy, there was a significant higher reduction of systolic function [ejection fraction (EF), fraction shortening (FS) and s wave] in Group II compared with Group I and non-significant reduction of diastolic function [E/A ratio or e/a ratio] in both Groups. Although serum troponin increases in both groups after doxorubicin therapy, the increase of troponin is significantly lower in group I compared with group II.

Conclusion: Silymarin decreased early Doxorubicin-induced left ventricular systolic function disturbances and can be recommended as an adjuvant drug in patients with ALL under doxorubicin therapy.

Recommendation: ‘Multicenter studies on a large number of patients with longer follow up’ periods to prove the protective role of silymarin in early and late Doxorubicin-induced cardiotoxicity.

Keywords: Silymarin, doxorubicin, cardiotoxicity, leukemia, lymphoblastic, children.

An, Q.; Fan, C.H.; Xu, S.M. Recent perspectives of pediatric leukemia - an update. Eur. Rev. Med. Pharmacol. Sci., 2017, 21(4)(Suppl.), 31-36.
Hagag, A.A.; Badraia, I.M.; Hassan, S.M.; Abd El-Lateef, A.E. Prognostic Impact of WT-1 Gene Expression in Egyptian Children with Acute Lymphoblastic Leukemia. Mediterr. J. Hematol. Infect. Dis., 2016, 8(1)e2016008
Ojha, S.; Al Taee, H.; Goyal, S.; Mahajan, U.B.; Patil, C.R.; Arya, D.S.; Rajesh, M. Cardioprotective Potentials of Plant-Derived Small Molecules against Doxorubicin Associated Cardiotoxicity. Oxid. Med. Cell. Longev., 2016, 20165724973
Elliott, P. Pathogenesis of cardiotoxicity induced by anthracyclines. Semin. Oncol., 2006, 33(3)(Suppl. 8), S2-S7.
Shan, K.; Lincoff, A.M.; Young, J.B. Anthracycline-induced cardiotoxicity. Ann. Intern. Med., 1996, 125(1), 47-58.
Giantris, A.; Abdurrahman, L.; Hinkle, A.; Asselin, B.; Lipshultz, S.E. Anthracycline-induced cardiotoxicity in children and young adults. Crit. Rev. Oncol. Hematol., 1998, 27(1), 53-68.
Oliveira, M.S.; Melo, M.B.; Carvalho, J.L.; Melo, I.M.; Lavor, M.S.L.; Gomes, D.A. Doxo-rubicin Cardiotoxicity and Cardiac Function Improvement After Stem Cell Therapy Diagnosed by Strain Echocardiography. J. Cancer Sci. Ther., 2013, 5(2), 52-57.
Kane, R.C.; McGuinn, W.D., Jr; Dagher, R.; Justice, R.; Pazdur, R. Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy. Oncologist, 2008, 13(4), 445-450.
Zhong, S.; Fan, Y.; Yan, Q.; Fan, X.; Wu, B.; Han, Y.; Zhang, Y.; Chen, Y.; Zhang, H.; Niu, J. The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: A meta-analysis (PRISMA) of randomized control trials. Medicine (Baltimore), 2017, 96(49)e9061
Surai, P.F. Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives. Antioxidants, 2015, 4(1), 204-247.
Frassová, Z.; Rudá-Kučerová, J. [Milk Thistle (Silybum Marianum) as a Supportive Phytotherapeutic Agent in Oncology]. Klin. Onkol., 2017, 30(6), 426-432.
Zou, H.; Zhu, X.X.; Zhang, G.B.; Ma, Y.; Wu, Y.; Huang, D.S. Silibinin: An old drug for hematological disorders. Onco-target., 2017, 11;8(51), 89307-89314.
Hagag, A.A. AbdElaal, A.M.; Elfaragy, M.S.; Hassan, S.M.; Elzamarany, E.A. Therapeutic value of black seed oil in methotrexate hepatotoxicity in Egyptian children with acute lymphoblastic leukemia. Infect. Disord. Drug Targets, 2015, 15(1), 64-71.
Margolin, J.F.; Rabin, K.R.; Steuber, C.P.; Poplack, D.G. Acute lymphoblastic leukemia, 6th ed; , 2011, pp. 518-565.
Ahmad, M.I.; Yadaw, B.K.; Sharma, N.; Varshney, A.K.; Sharma, L. Cardiac Troponin I Level in STEMI and Clinical Correlation with Left Ventricular Dysfunction in Indian Population. J. Cardiovasc. Dis. Diagn., 2013, 1, 116.
Joseph, S. Alpert.; Paul, W. Armstrong.; Jean-Pierre, Bassand.; George, Belle.; Sharma, L.; Bernard, R. Chaitman. Myocardial infarction redefined-a consensus document of the Joint European Socie-ty of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J. Am. Coll. Cardiol., 2000, 36, 959-969.
Schiller, N.B.; Shah, P.M.; Crawford, M.; DeMaria, A. b Devereux, R.; Feigenbaum, H.; Gutgesell, H.; Reichek, N.; Sahn, D.; Schnittger, I. Recommendations for quantification of left ven-tricle by two dimension echocardiography. J. Am. Soc. Echocardiogr., 1989, 2(5), 358-367.
Robert, O. Armstrong Echocardiography. Braunwald’s Heart Disease a Textbook of Cardiovascular Medicine., (7th ed. ), , 2006.
Ilham Al–Fakhri, F.; Firas Abid, T. Effect of maintenance therapy for childhood with ALL by combination of methotrexate and 6-mercaptopurine on the liver. Al-Mustansiriyah. J. Pharm. Sci., 2005, 2(2), 18-23.
Pui, C.H. Acute lymphoplastic leukemia: Overview. (17th ed. ),; , 2006.
Chauvenet, A.R.; Martin, P.L.; Devidas, M.; Linda, S.B.; Bell, B.A.; Kurtzberg, J.; Pullen, J.; Pettenati, M.J.; Carroll, A.J.; Shuster, J.J.; Camitta, B. Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children’s Oncology Group Study P9201. Blood, 2007, 110(4), 1105-1111.
Lanzkowsky, P.H. Lanzkowsky Philip (ed), Manual of Pediatric Hematology and Oncology, 6th Ed. Chap18: 2016; 367- 388.Churchill livingstane. Nek, London, Madrid. , 2016.
Cecen, E.; Dost, T.; Culhaci, N.; Karul, A.; Ergur, B.; Birincioglu, M. Protective effects of silymarin against doxorubicin-induced toxicity. Asian Pac. J. Cancer Prev., 2011, 12(10), 2697-2704.
Taleb, A.; Ahmad, K.A.; Ihsan, A.U.; Qu, J.; Lin, N.; Hezam, K.; Koju, N.; Hui, L.; Qilong, D. Antioxidant effects and mechanism of silymarin in oxidative stress induced cardiovascular diseases. Biomed. Pharmacother., 2018, 102, 689-698.
Rašković, A.; Stilinović, N.; Kolarović, J.; Vasović, V.; Vukmirović, S.; Mikov, M. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Molecules, 2011, 16(10), 8601-8613.
Aapro, M.; Bernard-Marty, C.; Brain, E.G.; Batist, G.; Erdkamp, F.; Krzemieniecki, K.; Leonard, R.; Lluch, A.; Monfardini, S.; Ryberg, M.; Soubeyran, P.; Wedding, U. Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper. Ann. Oncol., 2011, 22(2), 257-267.
Soucek, P.; Kondrova, E.; Hermanek, J.; Stopka, P.; Boumendjel, A.; Ueng, Y.F.; Gut, I. New model system for testing effects of flavonoids on doxorubicin-related formation of hydroxyl radicals. Anticancer Drugs, 2011, 22(2), 176-184.
Girish, C.; Koner, B.C.; Jayanthi, S.; Ramachandra Rao, K.; Rajesh, B.; Pradhan, S.C. Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice. Fundam. Clin. Pharmacol., 2009, 23(6), 735-745.
Sung, B.; Kunnumakkara, A.B.; Sethi, G.; Anand, P.; Guha, S.; Aggarwal, B.B. Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model. Mol. Cancer Ther., 2009, 8(4), 959-970.
El-Shitany, N.A.; El-Haggar, S.; El-desoky, K. Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats. Food Chem. Toxicol., 2008, 46(7), 2422-2428.
Patel, N.; Joseph, C.; Corcoran, G.B.; Ray, S.D. Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicol. Appl. Pharmacol., 2010, 245(2), 143-152.
Avci, H.; Epikmen, E.T.; Ipek, E.; Tunca, R.; Birincioglu, S.S.; Akşit, H.; Sekkin, S.; Akkoç, A.N.; Boyacioglu, M. Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity. Exp. Toxicol. Pathol., 2017, 69(5), 317-327.
Tjeerdsma, G.; Meinardi, M.T.; van Der Graaf, W.T.; van Den Berg, M.P.; Mulder, N.H.; Crijns, H.J.; de Vries, E.G.; van Veldhuisen, D.J. Early detection of anthracycline induced cardiotoxicity in asymptomatic patients with normal left ventricular systolic function: autonomic versus echocardiographic variables. Heart, 1999, 81(4), 419-423.
Oreto, L.; Todaro, M.C.H.; Umland, M.M.; Kramer, C.; Qamar, R.; Carerj, S.; Khandheria, B.K.; Paterick, T.E. Use of echocardiography to evaluate the cardiac effects of therapies used in cancer treatment: what do we know? J. Am. Soc. Echocardiogr., 2012, 25(11), 1141-1152.
Chlopcíková, S.; Psotová, J.; Miketová, P.; Simánek, V. Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I. Silymarin and its flavonolignans. Phytother. Res., 2004, 18(2), 107-110.
Dodos, F.; Halbsguth, T.; Erdmann, E.; Hoppe, U.C. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin. Res. Cardiol., 2008, 97(5), 318-326.
Ganame, J.; Claus, P.; Uyttebroeck, A.; Renard, M.; D’hooge, J.; Bijnens, B.; Sutherland, G.R.; Eyskens, B.; Mertens, L. Myocardial dysfunction late after low-dose anthracycline treatment in asymptomatic pediatric patients. J. Am. Soc. Echocardiogr., 2007, 20(12), 1351-1358.
Vauzour, D.; Rodriguez-Mateos, A.; Corona, G.; Oruna-Concha, M.J.; Spencer, J.P. Polyphenols and human health: prevention of disease and mechanisms of action. Nutrients, 2010, 2(11), 1106-1131.
Ma, Q. Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol., 2013, 53, 401-426.
Chen, X-L.; Kunsch, C. Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. Curr. Pharm. Des., 2004, 10(8), 879-891.

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Year: 2019
Page: [133 - 140]
Pages: 8
DOI: 10.2174/1871526518666180803141827
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