Toxicology 310 (2013) 115–123 Contents lists available at SciVerse ScienceDirect Toxicology jo u r n al homep age: www.elsevier.com/locate/toxicol Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney Robert Domitrovi ´ c a,∗ , Olga Cvijanovi ´ c b , Ester Pernjak Pugel c , Gordana Blagojevi ´ c Zagorac d , Hana Mahmutefendi ´ c d , Marko ˇ Skoda d a Department of Chemistry and Biochemistry, Medical Faculty, University of Rijeka, Rijeka, Croatia b Department of Anatomy, Medical Faculty, University of Rijeka, Rijeka, Croatia c Department of Histology and Embryology, Medical Faculty, University of Rijeka, Rijeka, Croatia d Department of Physiology and Immunology, Medical Faculty, University of Rijeka, Rijeka, Croatia a r t i c l e i n f o Article history: Received 17 April 2013 Received in revised form 8 May 2013 Accepted 10 May 2013 Available online 14 June 2013 Keywords: Cisplatin nephrotoxicity Luteolin Oxidative/nitrosative stress Inflammation Apoptosis a b s t r a c t The aim of this study was to investigate the effects of flavone luteolin against cisplatin (CP)-induced kidney injury in mice. Luteolin at doses of 10 mg/kg was administered intraperitoneally (ip) once daily for 3 days following single CP (10 or 20 mg/kg) ip injection. Mice were sacrificed 24 h after the last dose of luteolin. The CP treatment significantly increased serum creatinine and blood urea nitrogen and induced pathohistological changes in the kidneys. Renal oxidative/nitrosative stress was evidenced by decreased glutathione (GSH) levels and increased 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) formation as well as cytochrome P450 2E1 (CYP2E1) expression. The CP administration triggered inflam- matory response in mice kidneys through activation of nuclear factor-kappaB (NF-B) and overexpression of tumor necrosis factor-alpha (TNF-) and cyclooxygenase-2 (COX-2). Simultaneously, the increase in renal p53 and caspase-3 expression indicated apoptosis of tubular cells. The administration of luteolin significantly reduced histological and biochemical changes induced by CP, decreased platinum (Pt) levels and suppressed oxidative/nitrosative stress, inflammation and apoptosis in the kidneys. These results suggest that luteolin is an effective nephroprotective agent, with potential to reduce Pt accumulation in the kidneys and ameliorate CP-induced nephrotoxicity. © 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Cisplatin (cis-diamminedichloroplatinum(II), CP) is one of the most effective anticancer drugs in the treatment of solid tumors (Yao et al., 2007). CP therapeutic effects on cancer cells occur pri- marily through reactive oxygen species (ROS)-mediated induction of apoptosis (Bragado et al., 2007). Unfortunately, administration of CP to patients is frequently associated with serious adverse effects, including kidney injury. Multiple pathophysiological disturbances, including oxidative stress, inflammation, necrosis and apoptotic cell death, have been attributed to CP-induced nephropathy, which is a major concern for its clinical application (Bischin et al., 2011; Mukhopadhyay et al., 2011). The kidneys are considered as a major route for CP excretion and primary site of its accumulation, which ∗ Corresponding author at: Department of Chemistry and Biochemistry, Medical Faculty, University of Rijeka, B. Branchetta 20, 51000 Rijeka, Croatia. Tel.: +385 51 651 135. E-mail address: robertd@medri.uniri.hr (R. Domitrovi ´ c). contributes to CP-induced nephrotoxicity (Arany and Safirstein, 2003). Various approaches to prevent side effects of CP treatment have been studied. Natural compounds that exert antioxidant and anti-inflammatory activity emerged as a promising candi- dates for amelioration of CP-induced nephrotoxicity (Arjumand and Sultana, 2011; Kang et al., 2011). Luteolin is a well-known phenolic compound, which exhibit numerous pharmacological activities, including antioxidant, anti-inflammatory and antimi- crobial (López-Lázaro, 2009). Luteolin also showed antitumor and tumor chemosensitizing activity both in vitro and in vivo (Fu et al., 2012; Lee et al., 2012; Yan et al., 2012; Ashokkumar and Sudhandiran, 2011; Shi et al., 2007). The potential usage of lute- olin in cancer therapy has been encouraged by recent findings that luteolin prevented acute kidney damage in mice caused by CP treat- ment, through down-regulation of the p53-dependent apoptotic pathway (Kang et al., 2011). Previously, we showed that luteolin ameliorated acute liver damage and hepatic fibrosis in mice (Domitrovi ´ c et al., 2009a, b). In this study, we used a murine model of acute CP-induced kidney injury to examine antioxidative, 0300-483X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tox.2013.05.015