Abstract
This study presents experimental data on the effects of the tetraethylammonium salt of salinomycinic acid (Sal) on Cd-induced hepatotoxicity and renal dysfunction in Cd-treated mice compared to those of meso-2,3-dimercaptosuccinic acid (DMSA). Forty 60-day-old male ICR mice were randomized into five groups: control group (untreated mice), Cd group (Cd(II) acetate 20 mg/kg body weight provided orally once per day for 14 days), Cd + DMSA group (exposed to Cd(II) acetate as the Cd-exposed group followed by DMSA 20 mg/kg body weight provided orally once per day for 14 days), and Cd + Sal group (exposed to Cd(II) acetate as the Cd-exposed group followed by Sal 20 mg/kg body weight once per day for 14 days). Cd intoxication of mice induced significant liver and kidney injury and a significant elevation of the concentration of Cd in both organs. Treatment of Cd-exposed mice with DMSA or Sal restored the levels of the renal and hepatic functional markers and significantly decreased the concentration of the toxic metal ion in both organs. Administration of Sal improved Cd-induced alterations of the endogenous levels of the essential metal ions. Histological studies revealed that the antibiotic more effectively ameliorated the Cd effect on the liver morphology compared to DMSA. Taken together, the results confirm that the anticancer agent salinomycin is a promising antidote to Cd poisoning.
Similar content being viewed by others
References
Aaseth J, Grisponi G, Anderson O (2016) Chelation therapy in the treatment of metal intoxication 1st edition. Elsevier Inc., Amsterdam
Adaramoye OA, Akanni OO (2016) Modulatory effects of methanol extract of Artocarpus altilis (Moraceae) on cadmium-induced hepatic and renal toxicity in male Wistar rats. Pathophysiology 23(1):1–9. https://doi.org/10.1016/j.pathophys.2015.07.003
Antoszczak M, Huczyński A (2015) Anticancer activity of polyether ionophore-Salinomycin. Anti Cancer Agents Med Chem 15(5):575–591. https://doi.org/10.2174/1871520615666150101130209
Begic A, Djuric A, Ninkovic M, Stevanovic I, Djurdjevic D, Pavlovic M, Jelic K, Pantelic A, Zebic G, Dejanovic B, Stanojevic I, Vojvodic D, Milosavljevic P, Djukic M, Saso L (2017) Disulfiram moderately restores impaired hepatic redox status of rats subchronically exposed to cadmium. Enzyme Inhib Med Chem 2(1):478–489
Blanusa M, Varnai VM, Piasek M, Kostial K (2005) Chelators as antidotes of metal toxicity: therapeutic and experimental aspects. Curr Med Chem 12(23):2771–2794. https://doi.org/10.2174/092986705774462987
Blaurock-Busch E, Busch YM (2014) Comparison of chelating agents DMPS, DMSA and EDTA for the diagnosis and treatment of chronic metal exposure. Br J Med Med Res 4(9):1821–1835. https://doi.org/10.9734/BJMMR/2014/6875
Bridges CC, Zalups RK (2005) Molecular and ionic mimicry and the transport of toxic metals. Toxicol Appl Pharmacol 204(3):274–308. https://doi.org/10.1016/j.taap.2004.09.007
DelRaso NJ, Foy BD, Gearhart JM, Frazier JM (2003) Cadmium uptake kinetics in rat hepatocytes: correction for albumin binding. Toxicol Sci 72(1):19–30. https://doi.org/10.1093/toxsci/kfg009
Djukić-Cosić D, Curcić Jovanović M, Plamenac Bulat Z, Ninković M, Malicević Z, Matović V (2008) Relation between lipid peroxidation and iron concentration in mouse liver after acute and subacute cadmium intoxication. J Trace Elem Med Biol 22(1):66–72. https://doi.org/10.1016/j.jtemb.2007.09.024
Dkhil MA, Al-Quraishy S, Diab MM, Othman MS, Aref AM, Abdel Moneim AE (2014) The potential protective role of Physalis peruviana L. fruit in cadmium-induced hepatotoxicity and nephrotoxicity. Food Chem Toxicol 74:98–106. https://doi.org/10.1016/j.fct.2014.09.013
Erdem O, Yazihan N, Kocak MK, Sayal A, Akcil E (2015) Influence of chronic cadmium exposure on the tissue distribution of copper and zinc and oxidative stress parameters in rats. Toxicol Ind Health 32(8):1505–1514. https://doi.org/10.1177/0748233714566875
Flora SJ, Pachauri V (2010) Chelation in metal intoxication. Int J Environ Res Public Health. 7(7):2745–88. https://doi.org/10.3390/ijerph7072745
Fujishiro H, Okugaki S, Kubota K, Fujiyama T, Miyataka H, Himeno S (2009) The role of ZIP8 down-regulation in cadmium-resistant metallothionein-null cells. J Appl Toxicol 9(5):367–373
He L, Wang B, Hay EB, Nebert DW (2009) Discovery of ZIP transporters that participate in cadmium damage to testis and kidney. Toxicol Appl Pharmacol 238(3):250–257. https://doi.org/10.1016/j.taap.2009.02.017
Hogervorst J, Plusquin M, Vangronsveld J, Nawrot T, Cuypers A, Van HE, Roels HA, Carleer R, Staessen JA (2007) House dust as possible route of environmental exposure to cadmium and lead in the adult general population. Environ Res 103(1):30–37. https://doi.org/10.1016/j.envres.2006.05.009
Ivanova Ju, Pantcheva I, Mitewa M, Simova S, Tanabe M, and Osakada K (2010) Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin. Chem Centr J 2011, 5:52, 1, DOI: https://doi.org/10.1186/1752-153X-5-52
Ivanova J, Pantcheva IN, Zhorova R, Momekov G, Simova S, Stoyanova R, Zhecheva E, Ivanova S, Mitewa M (2012a) Synthesis, spectral properties, antibacterial and antitumor activity of salinomycin complexes with the transition metal ions Co(II), Ni(II), Cu(II) and Zn(II). J. Chem Chem Eng 6(6):551–562
Ivanova J, Gluhcheva Y, Kamenova K, Arpadjan S, Mitewa M (2012b) The tetraethylammonium salt of monensic acid—an antidote for subacute cadmium intoxication: a study using an ICR mouse model. J Trace Elem Med Biol 26(4):279–284
Ivanova J, Gluhcheva Y, Kamenova K, Arpadjan S, Mitewa M (2014) Monensin ameliorates Cd-induced hepatic injury in mice, subjected to subacute Cd intoxication. Biotechnol Biotechnol Eq 28(1):147–152. https://doi.org/10.1080/13102818.2014.901673
Järup L, Åkesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238(3):201–208. https://doi.org/10.1016/j.taap.2009.04.020
Järup L, Berglund M, Elinder CG, Nordberg G, Vahter M (1998) Health effects of cadmium exposure—a review of the literature and a risk estimate. Scand J Work Environ Health 24(Suppl 1):1–51
Jung HY, Seo DW, Hong CO, Kim JY, Yang SY, Lee KW (2015) Nephroprotection of plantamajoside in rats treated with cadmium. Environ Toxicol Pharmacol 39(1):125–136. https://doi.org/10.1016/j.etap.2014.11.012
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8(6):e1000412. https://doi.org/10.1371/journal.pbio.1000412
Klassen CD, Liu J (1997) Role of methallothionein in cadmium-induced hepatotoxicity and nephrotoxicity. Drug Metab Rev 29(1–2):79–102. https://doi.org/10.3109/03602539709037574
Liu J, Liu Y, Habeebu SS, Klaassen CD (1998) Susceptibility of MT-null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex. Toxicol Sci 46(1):197–203. https://doi.org/10.1006/toxs.1998.2541
Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ (2006) Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci U S A 103(37):13612–13617. https://doi.org/10.1073/pnas.0606424103
Luo T, Liu G, Long M, Yang J, Song R, Wang Y, Yuan Y, Bian J, Liu X, Gu J, Zou H, Liu Z (2016) Treatment of cadmium-induced renal oxidative damage in rats by administration of alpha-lipoic acid. Environ Sci Pollut Res Int 24(2):1832–1844. https://doi.org/10.1007/s11356-016-7953-x
Mai TT, Hamaï A, Hienzsch A, Cañeque T, Müller S, Wicinski J, Cabaud O, Leroy C, David A, Acevedo V, Ryo A, Ginestier C, Birnbaum D, Charafe-Jauffret E, Codogno P, Mehrpour M, Rodriguez R (2017) Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem 9(10):1025–1033. https://doi.org/10.1038/nchem.2778
Nakagawa J, Oishi S, Suzuki J, Tsuchiya Y, Ando M, Fujimoto Y (2004) Effects of long-term ingestion of cadmium-polluted Rice or low-dose cadmium-supplemented diet on the endogenous copper and zinc balance in female rats. J Health Sci 50(1):92–96. https://doi.org/10.1248/jhs.50.92
Navaneethan D, Rasool M (2014) p-Coumaric acid, a common dietary polyphenol, protects cadmium chloride-induced nephrotoxicity in rats. Ren Fail 36(2):244–251. https://doi.org/10.3109/0886022X.2013.835268
Naujokat C, Steinhart R, (2012) Salinomycin as a drug for targeting human cancer stem cells, J Biomed Biotechnol, 2012, Article ID 950658.
Nomiyama K, Sugata Y, Nomiyama H, Yamamoto A (1976) Dose response relationship for cadmium. In: Nordberg GF (ed) Effects and dose response relationship of toxic metals. Elsevier Science, Amsterdam, pp 380–385
Prabu SM, Shagirtha K, Renugadevi J (2011) Naringenin in combination with Vitamin C and E partially protects oxidative stress-mediated hepatic injury in cadmium-intoxicated rats. J Nutr Sci Vitaminol 57(2):177–185. https://doi.org/10.3177/jnsv.57.177
Prozialeck WC, Edwards JR (2007) Cell adhesion molecules in chemically-induced renal injury. Pharmacol Ther 114(1):74–93. https://doi.org/10.1016/j.pharmthera.2007.01.001
Prozialeck WC, Edwards JR, Lamar PC, Liu J, Vaidya VS, Bonventre JV (2009) Expression of kidney injury molecule-1 (Kim-1) in relation to necrosis and apoptosis during the early stages of Cd-induced proximal tubule injury. Toxicol Appl Pharmacol 238(3):306–314. https://doi.org/10.1016/j.taap.2009.01.016
Prozialeck WC, Edwards JR (2012) Mechanisms of cadmium-induced proximal tubule injury: new insights with implications for biomonitoring and therapeutic interventions. J Pharmacol Exp Ther 343(1):2–12. https://doi.org/10.1124/jpet.110.166769
Prozialeck WC, Lamar PC, Edwards JR (2016) Effects of subchronic cadmium exposure on levels of copper, selenium, zinc, iron and other essential metals in rat renal cortex. Toxicol Report 3:740–746. https://doi.org/10.1016/j.toxrep.2016.09.005
Rani A, Kumar A, Lal A, Pant M (2014) Cellular mechanisms of cadmium-induced toxicity: a review. Int J Environ Health Res 24(4):378–399. https://doi.org/10.1080/09603123.2013.835032
Rinaldi M, Micali A, Marini H, Adamo EB, Puzzolo D, Pisani A, Trichilo V, Altavilla D, Squadrito F, Minutoli L (2017) Cadmium, organ toxicity and therapeutic approaches. A review on brain, kidney and testis damage. Curr Med Chem, in press 24. https://doi.org/10.2174/0929867324666170801101448.
Souza V, Bucio L, Gutiérrez-Ruiz MC (1997) Cadmium uptake by a human hepatic cell line (WRL-68 cells). Toxicology 120(3):215–220. https://doi.org/10.1016/S0300-483X(97)00057-7
Suwazono Y, Kido T, Nakagawa H, Nishijo M, Honda R, Kobayashi E, Dochi M, Nogawa K (2009) Biological half-life of cadmium in the urine of inhabitants after cessation of cadmium exposure. Biomarkers 14(2):77–81. https://doi.org/10.1080/13547500902730698
Tomaszewska E, Winiarska-Mieczan A, Dobrowolski P (2015) Hematological and serum biochemical parameters of blood in adolescent rats and histomorphological changes in the jejunal epithelium and liver after chronic exposure to cadmium and lead in the case of supplementation with green tea vs black, red or white tea. Exp Toxicol Pathol 67(5-6):331–339. https://doi.org/10.1016/j.etp.2015.02.005
Varoni MV, Pasciu V, Gadau SD, Baralla E, Serra E, Palomba D, Demontis MP (2017) Possible antioxidant effect of Lycium barbarum polysaccharides on hepatic cadmium-induced oxidative stress in rats. Environ Sci Pollut Res Int 24(3):2946–2955. https://doi.org/10.1007/s11356-016-8050-x.
Acknowledgements
The authors are grateful to the Sofia University “St. Kliment Ohridski” Science Fund (grant №5/2016, PI: Juliana Ivanova) and to the European Social Fund and Republic of Bulgaria, Operational Programme “Human Resources Development” 2007-2013 framework, grant № BG051PO001-3.3.06-0048 from 04.10.2012 for the financial support of this study. The authors thank Professor S. Arpadjan for the atomic absorption analysis of the mouse tissues. The authors are grateful to Assoc. Prof. A. Nakov, P. Dorkov (BIOVET Ltd., Bulgaria) for supplying the sodium salinomycin.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This experimental protocol was approved by the Ethics Committee of the Institute of Experimental Morphology, Pathology and Anthropology with the Museum of the Bulgarian Academy of Science (approval number: 15/03/2016).
Conflict of interest statement
The authors declare that they have no conflict of interest.
Additional information
Responsible editor: Philippe Garrigues
Rights and permissions
About this article
Cite this article
Kamenova, K., Gluhcheva, Y., Vladov, I. et al. Ameliorative effect of the anticancer agent salinomycin on cadmium-induced hepatotoxicity and renal dysfunction in mice. Environ Sci Pollut Res 25, 3616–3627 (2018). https://doi.org/10.1007/s11356-017-0755-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-017-0755-y