Biological alterations in renal and hepatic tissues by a novel gold (III) anti-cancerous compound

Document Type : Original Article

Authors

1 Department of Pathology, College of Medicine and King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

2 Department of Pharmacology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

3 Department of Chemistry, King Fahd University of Petroleum & Minerals, Dhahran, Saudi Arabia

4 Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

Abstract

Objective(s): Newer organo-metallic, specifically gold (III) complexes with multiple ligands are currently being formulated with primary focus of having increased anti-cancerous properties and decreased cytotoxicity. In this study, histological toxicity profile of a newly formulated anti-cancerous gold (III) compound [trans-(±)-1,2-(DACH)2Au]Cl3 Bis(trans-1,2-Diaminocyclohexane) was investigated by evaluation of kidney and liver tissues of treated rats.
Materials and Methods: This is a quasi-experimental study. In acute toxicity component of the study, (n = 16) male rats weighing between 200–250 g were administered single, variable concentration of the gold (III) compound, [trans-(±)-1,2-(DACH)2Au]Cl3 Bis(trans-1,2-Diaminocyclohexane) to determine LD50 (dose that is lethal to 50% of rats). An IP injection of 2.3 mg/kg (equivalent to 1/10 of LD50) was injected for 14 consecutive days to (n=10) male rats in the sub-acute component of the study. Autopsy preservation of liver and kidney tissue in buffered formalin, sample processing, histopathological evaluation, and comparison with unremarkable controls (n=5) was conducted sequentially.
Results: A dose of 2.3 mg/kg did not produce any tubular necrosis in kidney specimens. Mild interstitial inflammation with prominence of plasma cells was the main histological alteration. Plasmacytic pyelitis was also seen. Varying extents of cytoplasmic vacuolization and mild focal lobular and portal inflammation were predominant hepatic microscopic findings.
Conclusion: [trans-(±)-1,2-(DACH)2Au]Cl3 Bis(trans-1,2-Diaminocyclohexane) produced no histological damage in renal and hepatic tissues of rats. This very limited sample animal-based study points to the relative safety of this new gold compound. However, there is a need to compare this compound with established drugs in a comparative non-animal based study.

Keywords

Main Subjects


1. Nardon C, Boscutti G, Fregona D. Beyond platinums: gold complexes as anticancer agents. Anticancer Res 2014; 34:487-492.
2. Astolfi L, Ghiselli S, Guaran V, Chicca M, Simoni E, Olivetto E, et al. Correlation of adverse effects of cisplatin administration in patients affected by solid tumours: a retrospective evaluation. Oncol Rep 2013; 29:1285-1292.
3. Olszewski U, Hamilton G.A better platinum-based anticancer drug yet to come?. Anticancer Agents Med Chem 2010; 10:293-301.
4. Janković SM, Djeković A, Bugarčić Z, Janković SV, Lukić G, Folić M, et al. Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct. Biometals 2012; 25:919-925.
5. Gabbiani C, Casini A, Messori L. Gold (III) compounds as anticancer drugs. Gold Bull 2007; 40:73-81.
6. Kalayda GV, Wagner CH, Jaehde U. Relevance of copper transporter 1 for cisplatin resistance in human ovarian carcinoma cells. J Inorg Biochem 2012; 116:1-10.
7. Buckley RG, Elsome AM, Fricker SP, Henderson GR, Theobald BR, Parish RV, et al. Antitumor properties of some 2-[(dimethylamino)methyl]phenylgold(III) complexes. J Med Chem 1996; 39:5208-5214.
8. Ahmed A, Al Tamimi DM, Isab AA, Alkhawajah AM, Shawarby MA. Histological changes in kidney and liver of rats due to gold (III) compound [Au(en)Cl(2)]Cl. PLoS One 2012; 7:e51889.
9. Al-Jaroudi SS, Monim-ul-Mehboob M, Altaf M, Fettouhi M, Wazeer MIM, Altuwaijri S, et al. Synthesis, Spectroscopic Characterization, X-ray structure and Electrochemistry of New Bis(1,2-Diaminocyclohexane)Gold(III) Chloride Compounds and their Anticancer Activities against PC3 and SGC7901Cancer Cell lines. New J Chem 2014; 38:3199-3211.
10. Miller LC, Tainter MI. Estimation of LD50 or ED50 values and their errors using Log-Probit graph paper. Proc Soc Expt Biol Med 1937; 57:261-264.
11. Underwood JCE. Histochemistry, Theoretical and Applied. Vol. 2: Analytical technology Pearse AGE. Fourth edition. Churchill Livingstone, Edinburgh 1985.
12. Zhang J, Brown RP, Shaw M, Vaidya VS, Zhou Y, Espandiari P, et al. Immunolocalization of Kim-1, RPA-1, and RPA-2 in Kidney of Gentamicin-, Mercury-, or Chromium-treated Rats: Relationship to Renal Distributions of iNOS and Nitrotyrosine. Toxicol Pathol 2008; 36:397-409.
13. Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009; 62:481-492.
14. Arsenijević M, Milovanovic M, Volarevic V, Djeković A, Kanjevac T, Arsenijević, et al.Cytotoxicity of gold(III) complexes on A549 human lung carcinoma epithelial cell line. Med Chem 2012; 8:2-8.
15. Basu A, Krishnamurthy S. Cellular responses to Cisplatin-induced DNA damage. J Nucleic Acids 2010:201367.
16. Lameire N. Nephrotoxicity of recent anti-cancer agents. Clin Kidney J 2014; 7:11-22.
17. Perazella MA, Moeckel GW. Nephrotoxicity from chemotherapeutic agents:
clinical manifestations, pathobiology, and prevention/therapy. Semin Nephrol 2010; 30:570-581.
18. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008; 73:994-1007.
19. Aldinucci D, Lorenzon D, Stefani L, Giovagnini L, Colombatti A, Fregona D. Antiproliferative and apoptotic effects of two new gold (III) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro. Anticancer Drugs 2007; 18:323-332.
20. Markowitz GS, Nasr SH, Stokes MB, D’Agati VD. Treatment with IFN-{alpha},-{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2010; 5:607-615.
21. Ciarimboli G, Holle SK, Vollenbröcker B, Hagos Y, Reuter S, Burckhardt G, et al. New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2. Mole pharm 2010; 8:270-279.
22. Glezerman IG, Pietanza MC, Miller V, Seshan SV. Kidney tubular toxicity of maintenance pemetrexed therapy. Am J Kidney Dis 2011; 58:817-820.
23. Perazella MA. Crystal-induced acute renal failure. Am J Med 1999; 106:459-465.
24. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immuno stimulation by anticancer drugs. Nat Rev Drug Discov 2012; 11:215-233.
25. Avci A, Cetin R, Erguder IB, Devrim E, Kilicoglu B, Candir O, et al. Cisplatin Causes Oxidation in Rat Liver Tissues: Possible Protective Effects of Antioxidant Food Supplementation. Turk J Med Sci 2008; 38:117-120.
26. Grigorian A, O’Brien CB. Hepatotoxicity Secondary to Chemotherapy. J Clin Transl Hepatol 2014; 2:95-102.
27. Tsui W MS. Drug-associated changes in the liver. Curr Diagn Pathol 2003; 9:96-104.
28. Lefkowitch JH. Histological assessment of cholestasis. Clin Liver Dis 2004; 8:27-40.
29. Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths?. Hepatology 2006; 43:31-44.
30. Bender C, Agarwala S, Tarhini A, Shipe-Spotloe J, Smelko B, Donnelly S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002; 20:3703-3718.
31. Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metstatic colorectal cancer. Ann Oncol 2004; 15:460-466.
32. Rothbarth J, Pigil MEJ, Vahrmeijer AL. Isolated hepatic perfusion with high-dose melphalan for the treatment of colorectal metastasis confined to the liver. Br J Surg 2003; 90:1391-1397.
33. Benjamin RS, Wiernik PH, Bachur NR. Adriamycin chemotherapy-efficacy, safety, and pharmacologic basis of an intermittent single high-dosage schedule. Cancer 1974; 33:19-27.
34. Tran A, Housset C, Boboc B, Tourani JM, Carnot F, Berthelot P. Etoposide (VP 16-213) induced hepatitis. Report of three cases following standard-dose treatments. J Hepatol 1991; 12:36-39.
35. Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. Cancer Treat Rev 2013; 39:199-206.
36. Liu J, Liu Y, Habeebu SS, Klaassen CD. Metallothionein (MT)-null mice are sensitive to cisplatin-induced hepatotoxicity. Toxicol Appl Pharmacol 1998; 149:24-31.
37. Martins NM, Santos NA, Curti C, Bianchi ML, Santos AC. Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. J Appl Toxicol 2008; 28:337-344.
38. Kart A, Cigremis Y, Karaman M, Ozen H. Caffeic acid phenethyl ester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit. Exp Toxicol Pathol 2010; 62:45-52.
39. Li X, Elwell MR, Ryan AM, Ochoa R. Morphogenesis of postmortem hepatocyte vacuolation and liver weight increases in Sprague-Dawley rats. Toxicol Pathol 2003; 31:682-688.