Abstract
Cisplatin is an antineoplastic agent used in the treatment of various types of solid tumors. Despite the dose-dependency of its antineoplastic effect, the high risk for nephrotoxicity frequently precludes the use of higher doses. α-Linolenic acid (ALA), a carboxylic acid having three cis double bonds, is an essential fatty acid required for health and can be acquired via foods that contain ALA or supplementation of foods high in ALA. Previous studies have shown that ALA demonstrates anti-cancer, anti-inflammatory, and anti-oxidative effects. In this study, we show the protective effect of ALA on cisplatin-induced renal toxicity associated with oxidative stress in mice using biochemical parameters. The mice were randomly assigned into four experimental groups. Group 1 (control group) were administered physiological saline solution for 9 days; group 2 (ALA group) received 200 mg/kg alpha-linolenic acid via gavage for 9 days; group 3 (CIS group) received 100 mg/kg intraperitoneal (i.p.) CIS for 9 days; and group 4 (ALA + CIS group) received 100 mg/kg i.p. CIS and followed by ALA 200 mg/kg via gavage for 9 days. Alpha-linolenic acid significantly reduced the expression of myeloperoxidase (MPO), phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the ALA + CIS group compared to the CIS group. Furthermore, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) quantities were significantly elevated in the ALA + CIS group when compared to the CIS group. ALA significantly decreased the levels of Bax and cleaved caspase-3, while significantly increasing the level of bcl-2, an anti-apoptotic protein, in the ALA + CIS group than in the CIS group. Finally, histopathological examination in renal tissue showed that the significant edematous damage induced by CIS administration alone was reduced in ALA + CIS group. In conclusion, our findings show that ALA is beneficial to CIS-induced nephrotoxicity in mice via its anti-inflammatory and anti-oxidative effects.
Similar content being viewed by others
References
Aebi H (1974) Catalase. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Academic Press, New York, pp 673–677
Calder PC (2013) Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol 75:645–662
Camuesco D, Galvez J, Nieto A, Comalada M, Rodriguez-Cabezas ME, Concha A, Xaus J, Zarzuelo A (2005) Dietary olive oil supplemented with fish oil, rich in EPA and DHA (n-3) polyunsaturated fatty acids, attenuates colonic inflammation in rats with DSS-induced colitis. J Nutr 135:687–694
Carotenuto F, Coletti D, Di Nardo P, Teodori L (2016) α-Linolenic acid reduces TNF-induced apoptosis in C2C12 myoblasts by regulating expression of apoptotic proteins. Eur J Transl Myol 26:6033
Chirino YI, Pedraza-Chaverri J (2009) Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol 61:223–242
Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378
Esposito E, Cuzzocrea S (2007) The role of nitric oxide synthases in lung inflammation. Curr Opin Invest Dr 8:899–909
Florea AM, Büsselberg D (2011) Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 3:1351–1371
Galecki P, Galecka E, Maes M, Chamielec M, Orzechowska A, Bobinska K, Lewinski A, Szemraj J (2012) The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder. J Affect Disord 138:360–366
Ganguly R, Hasanally D, Stamenkovic A, Maddaford TG, Chaudhary R, Pierce GN, Ravandi A (2018) Alpha linolenic acid decreases apoptosis and oxidized phospholipids in cardiomyocytes during ischemia/reperfusion. Mol Cell Biochem 437:163–175
Hartmann JT, Kollmannsberger C, Kanz L, Bokemeyer C (1999) Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer 83:866–869
Hassan A, Ibrahim A, Mbodji K, Coeffier M, Ziegler F, Bounoure F, Chardigny JM, Skiba M, Savoye G, Dechelotte P, Marion-Letellier R (2010) An alpha-linolenic acid-rich formula reduces oxidative stress and inflammation by regulating NF-kappaB in rats with TNBS-induced colitis. J Nutr 140:1714–1721
Hillegass LM, Griswold DE, Brickson B, Albrightsonwinslow C (1990) Assessment of myeloperoxidase activity in whole rat-kidney. J Pharmacol Method 24:285–295
Kadikoylu G, Bolaman Z, Demir S, Balkaya M, Akalin N, Enli Y (2004) The effects of desferrioxamine on cisplatin-induced lipid peroxidation and the activities of antioxidant enzymes in rat kidneys. Hum Exp Toxicol 23:29–34
Kaplan HM, Izol V, Arıdogan IA, Olgan E, Yegani AA, Pazarcı P, Singirik E (2016) Protective effect of alpha-linolenic acid on gentamicin induced nephrotoxicity in mice. Int J Pharm 12:562–566
Kaplan HM, Singirik E, Erdogan KE, Doran F (2017) Protective effect of alpha-linolenic acid on gentamicin-induced ototoxicity in mice. Somatosens Mot Res 34:145–150
Maliakel DM, Kagiya TV, Nair CK (2008) Prevention of cisplatin-induced nephrotoxicity by glucosides of ascorbic acid and alpha-tocopherol. Exp Toxicol Pathol 60:521–527
Malis CD, Bonventre JV (1986) Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage. J Biol Chem 261:14201–14208
Miller RP, Tadagavadi RK, Ramesh G, Reeves WB (2010) Mechanisms of cisplatin nephrotoxicity. Toxins (Basel) 2:2490–2518
Mistry P, Lee C, McBrien DC (1989) Intracellular metabolites of cisplatin in the rat kidney. Cancer Chemother Pharmacol 24:73–79
Nelson TL, Hokanson JE, Hickey MS (2011) Omega-3 fatty acids and lipoprotein associated phospholipase A2 in healthy older adult males and females. Eur J Nutr 50:185–193
Oh GS, Kim HJ, Shen A, Lee SB, Khadka D, Pandit A, So HS (2014) Cisplatin-induced kidney dysfunction and perspectives on improving treatment strategies. Electrolyte Blood Press 12:55–65
Paglia DE (1989) Erythroenzymopathies—1960s in retrospect—a citation classic commentary on studies on the quantitative and qualitative characterization of erythrocyte glutathione-peroxidase by Paglia DE. Clin Med 8:16
Poljakovic M, Svensson ML, Svanborg C, Johansson K, Larsson B, Persson K (2001) Escherichia coli-induced inducible nitric oxide synthase and cyclooxygenase expression in the mouse bladder and kidney. Kidney Int 59:893–904
Ren J, Chung SH (2007) Anti-inflammatory effect of alpha-linolenic acid and its mode of action through the inhibition of nitric oxide production and inducible nitric oxide synthase gene expression via NF-kappaB and mitogen-activated protein kinase pathways. J Agric Food Chem 55:5073–5080
Richard D, Kefi K, Barbe U, Bausero P, Visioli F (2008) Polyunsaturated fatty acids as antioxidants. Pharmacol Res 57:451–455
Rordorf G, Koroshetz WJ, Bonventre JV (1991) Heat shock protects cultured neurons from glutamate toxicity. Neuron 7:1043–1051
Sahu BD, Tatireddy S, Koneru M, Borkar RM, Kumar JM, Kuncha M, Srinivas R, Sunder RS, Sistla R (2014) Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection. Toxicol Appl Pharm 277:8–20
Shi Y (2004) Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci 13:1979–1987
Simopoulos AP (2002) Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 21:495–505
Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500
Suphioglu C, De Mel D, Kumar L, Sadli N, Freestone D, Michalczyk A, Sinclair A, Ackland ML (2010) The omega-3 fatty acid, DHA, decreases neuronal cell death in association with altered zinc transport. FEBS Lett 584:612–618
Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86:271–278
Verma PK, Raina R, Sultana M, Singh M, Kumar P (2016) Total antioxidant and oxidant status of plasma and renal tissue of cisplatin-induced nephrotoxic rats: protection by floral extracts of Calendula officinalis Linn. Ren Fail 38:142–150
Vyas D, Laput G, Vyas AK (2014) Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Oncotargets Ther 7:1015–1023
Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin nephrotoxicity: a review. Am J Med Sci 334:115–124
Zhou H, Kato A, Miyaji T, Yasuda H, Fujigaki Y, Yamamoto T, Yonemura K, Takebayashi S, Mineta H, Hishida A (2006) Urinary marker for oxidative stress in kidneys in cisplatin-induced acute renal failure in rats. Nephrol Dial Transplant 21:616–623
Funding
This study has been funded by Cukurova University Scientific Research Projects Unit (FBA-2018-10148).
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
İstifli, E.S., Demir, E., Kaplan, H.M. et al. Alpha-linolenic acid confers protection on mice renal cells against cisplatin-induced nephrotoxicity. Cytotechnology 71, 905–914 (2019). https://doi.org/10.1007/s10616-019-00333-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10616-019-00333-2