1. bookVolume 69 (2019): Issue 2 (June 2019)
Journal Details
First Published
25 Mar 2014
Publication timeframe
4 times per year
access type Open Access

Investigation of the Effects of Artemisinin on Testis and Kidney Injury Induced by Doxorubicin

Published Online: 22 Jun 2019
Volume & Issue: Volume 69 (2019) - Issue 2 (June 2019)
Page range: 177 - 191
Received: 27 Feb 2019
Accepted: 17 May 2019
Journal Details
First Published
25 Mar 2014
Publication timeframe
4 times per year

Artemisinin, an antimalarial drug, has anticancer activity and possesses protective effects against several tissue injuries. The aim of the present study was to investigate the effects of artemisinin on doxorubicin-induced renal and testicular toxicity in rats. Doxorubicin was administered to rats at a single dose of 10 mg/kg body weight (b.w.) as a single intraperitoneal injection. Application of artemisinin was by using oral gavage feeding needle for 14 days at different specified doses (7 mg/kg and 35 mg/kg b.w.). At the end of the experiments, kidney and testis samples were collected and used for histopathological and immunohistochemical examinations. At histopathological examination, while hyperemia was the marked finding in kidney and testis of rats treated with doxorubicin only, no evidence of structural abnormalities showed in other groups. Immunohistochemical examination of the testes and kidneys demonstrated significantly increased expression of caspase-3, TNF-α, iNOS and NF-κB in rats treated with doxorubicin only. Artemisinin decreased the doxorubicin-induced overexpression of NF-κB, iNOS, TNFα and caspase-3 in these tissues of rats. Artemisinin can protect the kidney and testis against doxorubicin-induced nephrotoxicity and testotoxicity, probably through a decrease of caspase-3, TNF-α, iNOS and NF-κB expressions. It may be concluded that artemisinin has a potential for clinical use in the treatment of kidney and testis damage induced by doxorubicin. Further researches are required to determine the appropriate combination of artemisinin with doxorubicin.


1. Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, Boucek RJ: Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci U S A 1988, 85:3585-3589.10.1073/pnas.85.10.35852802582897122Search in Google Scholar

2. Warpe VS, Mali VR, Arulmozhi S, Bodhankar SL, Mahadik KR: Cardioprotective effect of ellagic acid on doxorubicin induced cardiotoxicity in wistar rats. J Acute Med 2015, 5:1-8.10.1016/j.jacme.2015.02.003Search in Google Scholar

3. Gorini S, De Angelis A, Berrino L, Malara N, Rosano G, Ferraro E: Chemotherapeutic drugs and mitochondrial dysfunction: Focus on doxorubicin, trastuzumab, and sunitinib. Oxid Med Cell Longev 2018, 758273010.1155/2018/7582730587887629743983Search in Google Scholar

4. Singal PK, Iliskovic N: Doxorubicin-induced cardiomyopathy. N Engl J Med 1998, 339:900-905.10.1056/NEJM1998092433913079744975Search in Google Scholar

5. Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C: Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2: Bax ratio. Cancer Res 2002, 62:4592-4598.Search in Google Scholar

6. McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM: Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther 2017, 31:63-75.10.1007/s10557-016-6711-0534659828185035Search in Google Scholar

7. Zilinyi R, Czompa A, Czegledi A, Gajtko A, Pituk D, Lekli I, Tosaki A: The cardioprotective effect of metformin in doxorubicin-induced cardiotoxicity: The Role of Autophagy. Molecules 2018, 23:1184.10.3390/molecules23051184610006129762537Search in Google Scholar

8. Kalender Y, Yel M, Kalender S: Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats: the effects of vitamin E and catechin. Toxicology 2005, 209:39-45.10.1016/j.tox.2004.12.00315725512Search in Google Scholar

9. Mostafa MG, Mima T, Ohnishi ST, Mori K: S-allylcysteine ameliorates doxorubicin toxicity in the heart and liver in mice. Planta Med 2000, 66:148-151.10.1055/s-2000-1112410763589Search in Google Scholar

10. Ayla S, Seckin I, Tanriverdi G, Cengiz M, Eser M, Soner BC, Oktem G: Doxorubicin induced nephrotoxicity: protective effect of nicotinamide. Int J. Cell Biol 2011, 201110.1155/2011/390238314077721789041Search in Google Scholar

11. Siswanto S, Arozal W, Juniantito V, Grace A, Agustini FD: The effect of mangiferin against brain damage caused by oxidative stress and inflammation induced by doxorubicin. HAYATI J Biosci 2016, 23:51-55.10.1016/j.hjb.2016.02.001Search in Google Scholar

12. Srdjenovic B, Milic-Torres V, Grujic N, Stankov K, Djordjevic A, Vasovic V: Antioxidant properties of fullerenol C60 (OH) 24 in rat kidneys, testes, and lungs treated with doxorubicin. Toxicol Mech Method 2010, 20:298-305.10.3109/15376516.2010.48562220491520Search in Google Scholar

13. Divya S, Madhuri D, Lakshman M, Reddy AG: Pathological and ultra-structural changes in testis of rats due to doxorubicin toxicity and its amelioration with quercetin. Int. J. Curr. Microbiol. App. Sci 2017, 6:2295-2306.10.20546/ijcmas.2017.607.330Search in Google Scholar

14. Vapa I, Torres VM, Djordjevic A, Vasovic V, Srdjenovic B, Simic VD, Popović JK: Effect of fullerenol C 60 (OH) 24 on lipid peroxidation of kidneys, testes and lungs in rats treated with doxorubicine. Eur J Drug Metab Pharmacokinet 2012, 37:301-307.10.1007/s13318-012-0092-y22527972Search in Google Scholar

15. Bilir EK, Tutun H, Sevin S, Kismali G, Yarsan E: Cytotoxic Effects of rhododendron ponticum l. extract on prostate carcinoma and adenocarcinoma cell line (DU145, PC3). Kafkas Univ Vet Fak Derg 2018, 24:451-457.10.9775/kvfd.2017.19219Search in Google Scholar

16. Keyvan E, Tutun H: Effects of carvacrol on Staphyloccus aureus isolated from bulk tank milk. Med Weter 2019, 75: 238-241.10.21521/mw.6211Search in Google Scholar

17. Shin SA, Moon S, Kim WY, Paek SM, Park H, Lee C: Structure-based classification and anti-cancer effects of plant metabolites. Int J Mol Sci 2018, 19: 2651.10.3390/ijms19092651616373530200668Search in Google Scholar

18. Tutun H, Koç N, Kart A: Plant essential oils used against some bee diseases. TURJAF 2018, 6:34-45.10.24925/turjaf.v6i1.34-45.1502Search in Google Scholar

19. Liao F: Discovery of artemisinin (qinghaosu). Molecules 2009, 14:5362-5366.10.3390/molecules14125362Search in Google Scholar

20. Abdin MZ, Alam P: Genetic engineering of artemisinin biosynthesis: prospects to improve its production. Acta Physiol Plant 2015, 37:33.10.1007/s11738-015-1771-5Search in Google Scholar

21. Zyad A, Tilaoui M, Jaafari A, Oukerrou MA, Mouse HA: More insights into the pharmacological effects of artemisinin. Phytother Res 2018, 32:216-229.10.1002/ptr.595829193409Search in Google Scholar

22. Crespo-Ortiz MP, Wei MQ: Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. J Biomed Biotechnol 2011, 2012:24759710.1155/2012/247597Search in Google Scholar

23. Wang XM, Zhang L, Ding GF, Wang QZ: Inhibitory effect of dihydroartemisinin on the growth of human prostate cancer PC-3M cells and its mechanism. Zhonghua Nan Ke Xue 2012, 18:590-594.Search in Google Scholar

24. Chou S, Marousek G, Auerochs S, Stamminger T, Milbradt J, Marschall M: The unique antiviral activity of artesunate is broadly effective against human cytomegaloviruses including therapy-resistant mutants. Antiviral Res 2011, 92:364-368.10.1016/j.antiviral.2011.07.018Search in Google Scholar

25. Gautam P, Upadhyay SK, Hassan W, Madan T, Sirdeshmukh R, Sundaram CS, Gade WN, Basir SF, Singh Y, Sarma PU: Transcriptomic and proteomic profile of Aspergillus fumigatus on exposure to artemisinin. Mycopathologia 2011, 172:331-4610.1007/s11046-011-9445-3Search in Google Scholar

26. Schultz TL, Hencken CP, Woodard LE, Posner GH, Yolken RH, Jones-Brando L, Carruthers VB: A thiazole derivative of artemisinin moderately reduces Toxoplasma gondii cyst burden in infected mice. J Parasitol 2014, 100:516-521.10.1645/13-451.1Search in Google Scholar

27. Want MY, Islamuddin M, Chouhan G, Ozbak HA, Hemeg HA, Dasgupta AK, Chattopadhyay AP, Afrin F: Therapeutic efficacy of artemisinin-loaded nanoparticles in experimental visceral leishmaniasis. Colloids Surf B Biointerfaces 2015, 130:215-221.10.1016/j.colsurfb.2015.04.013Search in Google Scholar

28. Wang KS, Li J, Wang Z, Mi C, Ma J, Piao LX, Xu GH, Li X, Jin, X: Artemisinin inhibits inflammatory response via regulating NF-κB and MAPK signaling pathways. Immunopharmacol Immunotoxicol 2017, 39:28-36.10.1080/08923973.2016.1267744Search in Google Scholar

29. Juteau F, Masotti V, Bessiere JM, Dherbomez M, Viano J: Antibacterial and antioxidant activities of Artemisia annua essential oil. Fitoterapia 2002, 73: 532-535.10.1016/S0367-326X(02)00175-2Search in Google Scholar

30. O’Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin-the debate continues. Molecules 2010; 15:1705–1721.10.3390/molecules15031705625735720336009Search in Google Scholar

31. Gu Y, Wang X, Wang X, Yuan M, Wu G, Hu J, Tang Y, Huang, C: Artemisinin attenuates post-infarct myocardial remodeling by down-regulating the NF-κB pathway. Tohoku J Exp Med 2012, 227:161-170.10.1620/tjem.227.16122729178Search in Google Scholar

32. Sun LH, Li HZ, Han LP, Jiang CM, Zhao YJ, Gao XX, Tian Y, Xu CQ: Effect of artemisinin on ischemia/reperfusion injury of isolated rat myocardium. Zhongguo Zhong Yao Za Zhi 2007, 32:1547-1551.Search in Google Scholar

33. Zhao X, Wang L, Zhang H, Zhang D, Zhang Z, Zhang J: Protective effect of artemisinin on chronic alcohol induced-liver damage in mice. Environ Toxicol Pharmacol 2017, 52:221-226.10.1016/j.etap.2017.04.00828448816Search in Google Scholar

34. Pugazhendhi A, Edison TNJI, Velmurugan BK, Jacob JA, Karuppusamy I: Toxicity of Doxorubicin (Dox) to different experimental organ systems. Life sci 2018, 200:26-3010.1016/j.lfs.2018.03.023Search in Google Scholar

35. Shivakumar P, Rani MU, Reddy AG, Anjaneyulu Y: A study on the toxic effects of doxorubicin on the histology of certain organs. Toxicol Int 2012, 19: 241.10.4103/0971-6580.103656Search in Google Scholar

36. Lui RC, Laregina MC, Herbold DR, Johnson FE: Testicular cytotoxicity of intravenous doxorubicin in rats. J Urol 1986, 136:940-943.10.1016/S0022-5347(17)45136-6Search in Google Scholar

37. Green DR, Llambi F: Cell death signaling. Cold Spring Harb Perspect Biol 2015, 7; a006080.10.1101/cshperspect.a006080Search in Google Scholar

38. Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol 2007, 35:495-516.10.1080/01926230701320337Search in Google Scholar

39. McIlwain DR, Berger T, Mak TW: Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 2013, 5:a008656.10.1101/cshperspect.a008656Search in Google Scholar

40. Baud V, Karin M: Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001, 11:372-377.10.1016/S0962-8924(01)02064-5Search in Google Scholar

41. Turner MD, Nedjai B, Hurst T, Pennington DJ: Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta Mol Cell Res 2014, 1843:2563-2582.10.1016/j.bbamcr.2014.05.01424892271Search in Google Scholar

42. Fan Y, Dutta J, Gupta N, Fan G, Gélinas C: Regulation of programmed cell death by NF-κB and its role in tumorigenesis and therapy. In Programmed cell death in cancer progression and therapy. Dordrecht: Springer; 2008, 223-25010.1007/978-1-4020-6554-5_1118437897Search in Google Scholar

43. Hatano E: Tumor necrosis factor signaling in hepatocyte apoptosis. J Gastroenterol Hepatol 2007, 22:S43-S44.10.1111/j.1440-1746.2006.04645.x17567463Search in Google Scholar

44. Liu T, Zhang L, Joo D, Sun SC: NF-κB signaling in inflammation. Signal Transduct Target Ther 2017, 2:17023.10.1038/sigtrans.2017.23Search in Google Scholar

45. Lechner M, Lirk P, Rieder J: Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. In Seminars in cancer biology Academic Press; 2005, 15:277-28910.1016/j.semcancer.2005.04.004Search in Google Scholar

46. Džoljić E, Grabatinić I, Kostić V: Why is nitric oxide important for our brain? Funct neurol 2015, 30:159.10.11138/FNeur/2015.30.3.159Search in Google Scholar

47. Kang JK, Lee YJ, No KO, Jung EY, Sung JH, Kim YB, Nam SY: Ginseng intestinal metabolite-I (GIM-I) reduces doxorubicin toxicity in the mouse testis. Reprod Toxicol 2002, 16:291-298.10.1016/S0890-6238(02)00021-7Search in Google Scholar

48. Deman A, Ceyssens B, Pauwels M, Zhang J, Houte KV, Verbeelen D, Van den Branden C: Altered antioxidant defence in a mouse adriamycin model of glomerulosclerosis. Nephrol Dial Transpl 2001, 16:147-150.10.1093/ndt/16.1.14711209009Search in Google Scholar

49. Benzer F, Kandemir FM, Kucukler S, Comaklı S, Caglayan C: Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage. Arch Physiol Biochem 2018, 124:448-457.10.1080/13813455.2017.142276629302997Search in Google Scholar

50. Heravi NE, Hosseinian S, Yazd ZNE, Shafei MN, Bideskan AE, Shahraki S, Noshahr ZS, Motejadded F, Beheshti F, Mohebbati R, Parhizgar S, Rad AK: Doxorubicin-induced renal inflammation in rats: Protective role of Plantago major. Avicenna J Phytomed 2018, 8:179.Search in Google Scholar

51. Rehman MU, Tahir M, Khan AQ, Khan R, Oday-O-Hamiza, Lateef A, Hassan SK, Rashid S, Ali N, Zeeshan M, Sultana S: D-limonene suppresses doxorubicin-induced oxidative stress and inflammation via repression of COX-2, iNOS, and NFκB in kidneys of Wistar rats. Exp Biol Med 2014, 239:465-476.10.1177/153537021352011224586096Search in Google Scholar

52. El-Sheikh AA, Morsy MA, Mahmoud MM, Rifaai RA, Abdelrahman AM: Effect of coenzyme-Q10 on doxorubicin-induced nephrotoxicity in rats. Adv Pharmacol Sci 2012, 2012.10.1155/2012/981461353399523346106Search in Google Scholar

53. Kabel AM: Zinc/alogliptin combination attenuates testicular toxicity induced by doxorubicin in rats: Role of oxidative stress, apoptosis and TGF-β1/NF-κB signaling. Biomed Pharmacother 2018, 97:439-449.10.1016/j.biopha.2017.10.14429091894Search in Google Scholar

54. Magalhães J, Ascensao A, Padrao AI, Aleixo IM, Santos-Alves E, Rocha-Rodrigues S, Ferreira A, Korrodi-Gregorio L, Vitorino R, Ferreira R, Fardilha M: Can exercise training counteract doxorubicin-induced oxidative damage of testis proteome? Toxicol lett 2017, 280:57-69.10.1016/j.toxlet.2017.08.01028818578Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo