Abstract
Growing evidence has been reported on adriamycin (ADR) hepatotoxicity in literature. Hepatotoxicity caused by the use of drugs has a serious undesirable effect in the cure of cancer patients that needs to be eliminated. The exact mechanism of ADR on non-cancerous tissue still remains to be a mystery. The zeolite (clinoptilolite) minerals form a complex group of aluminosilicates that often occur as accessory minerals in intermediate and basic rocks. In light of this information, we investigated the possible anti-inflammatory and anti-apoptotic effects of clinoptilolite in ADR that is inducing the toxicity in primary liver cell culture. Primary liver cell culture from rat was used in the study. We had three experiment groups including the following: (1) cells treated only with 50 μM ADR for 24 h, (2) cells treated with the 50 μM ADR for 24 h and then treated with 10−4 M zeolite for 1 h, and (3) cells were incubated with 50 μM ADR for 24 h and then incubated with 10−4 M zeolite for 24 h to test its long-term effects. After that, western blotting was performed in order to evaluate protein expression levels of several inflammation markers including IL-1β, tumor necrosis factor (TNF)-α, and nuclear factor kappa B (NF-κB), and immunohistochemistry was carried out to detect apoptosis in liver cell culture. Also, TdT–dUTP Terminal Nick-End Labeling (TUNEL) method was used for detecting apoptosis. We found elevated levels of inflammatory protein and apoptotic markers in ADR-administered cells (p < 0.05). Inflammatory and apoptotic markers decreased significantly after treated with zeolite (p < 0.05). The present study was pointed out that ADR causes hepatotoxicity via apoptosis and/or inflammation processes resulting from initiator NF-κB and TNF which causes proinflammatory mediators such as IL-1β. Elevation of inflammation might give rise to trigger apoptosis. Clinoptilolite counteracted the apoptosis and inflammation induced by ADR arising from the decrease in NF-κB, TNF-α, and IL-1β protein levels.
Similar content being viewed by others
References
Dursun N, Taskin E, Yerer Aycan MB, Sahin L (2011) Selenium-mediated cardioprotection against adriamycin-induced mitochondrial damage. Drug Chem Toxicol 34(2):199–207
Taskin E, Ozdogan K, Kunduz Kindap E, Dursun N (2014) The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity. Ren Fail 36(4):606–612
Singla S, Kumar NR, Kaur J (2014) In vivo studies on the protective effect of propolis on doxorubicin-induced toxicity in liver of male rats. Toxicol Int 21(2):191–195
Mohamed RH, Karam RA, Hagrass HA, Amer MG, Abd El-Haleem MR (2015) Anti-apoptotic effect of spermatogonial stem cells on doxorubicin-induced testicular toxicity in rats. Gene 561(1):107–114
Merzoug S, Toumi ML, Tahraoui A (2014) Quercetin mitigates adriamycin-induced anxiety- and depression-like behaviors, immune dysfunction, and brain oxidative stress in rats. Naunyn Schmiedeberg’s Arch Pharmacol 387(10):921–933
Guo R, Wu K, Chen J, Mo L, Hua X, Zheng D et al (2013) Exogenous hydrogen sulfide protects against doxorubicin-induced inflammation and cytotoxicity by inhibiting p38MAPK/NFkappaB pathway in H9c2 cardiac cells. Cell Physiol Biochem 32(6):1668–1680
Quiles JL, Huertas JR, Battino M, Mataix J, Ramirez-Tortosa MC (2002) Antioxidant nutrients and adriamycin toxicity. Toxicology 180(1):79–95
Monteiro JP, Oliveira PJ, Jurado AS (2013) Mitochondrial membrane lipid remodeling in pathophysiology: a new target for diet and therapeutic interventions. Prog Lipid Res 52(4):513–528
Bozcali E, Suzer O, Gursoy HN, Atukeren P, Gumustas KM (2009) Effects of erucic acid supplemented feeding on chronic doxorubicin toxicity in rats. Int J Clin Exp Med 2(4):337–347
Hoye AT, Davoren JE, Wipf P, Fink MP, Kagan VE (2008) Targeting mitochondria. Acc Chem Res 41(1):87–97
Mantawy EM, El-Bakly WM, Esmat A, Badr AM, El-Demerdash E (2014) Chrysin alleviates acute doxorubicin cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Eur J Pharmacol 728:107–118
Tinteri C, Potenza M, Rizzetto R (2012) Antimicrobial efficacy and longevity of silver + zeolite incorporating preinsulated ducts installed in real healthcare settings. J Prev Med Hyg 53(4):177–180
Krajisnik D, Stepanovic-Petrovic R, Tomic M, Micov A, Ibric S, Milic J (2014) Application of artificial neural networks in prediction of diclofenac sodium release from drug-modified zeolites physical mixtures and antiedematous activity assessment. J Pharm Sci 103(4):1085–1094
Muck-Seler D, Pivac N (2003) The effect of natural clinoptilolite on the serotonergic receptors in the brain of mice with mammary carcinoma. Life Sci 73(16):2059–2069
Pavelic K, Katic M, Sverko V, Marotti T, Bosnjak B, Balog T et al (2002) Immunostimulatory effect of natural clinoptilolite as a possible mechanism of its antimetastatic ability. J Cancer Res Clin Oncol 128(1):37–44
Montinaro M, Uberti D, Maccarinelli G, Bonini SA, Ferrari-Toninelli G, Memo M (2013) Dietary zeolite supplementation reduces oxidative damage and plaque generation in the brain of an Alzheimer’s disease mouse model. Life Sci 92(17–19):903–910
Ivkovic S, Deutsch U, Silberbach A, Walraph E, Mannel M (2004) Dietary supplementation with the tribomechanically activated zeolite clinoptilolite in immunodeficiency: effects on the immune system. Adv Ther 21(2):135–147
Zarkovic N, Zarkovic K, Kralj M, Borovic S, Sabolovic S, Blazi MP et al (2003) Anticancer and antioxidative effects of micronized zeolite clinoptilolite. Anticancer Res 23(2B):1589–1595
Alavijeh MS, Chishty M, Qaiser MZ, Palmer AM (2005) Drug metabolism and pharmacokinetics, the blood–brain barrier, and central nervous system drug discovery. NeuroRx 2(4):554–571
Ingawale DK, Mandlik SK, Naik SR (2014) Models of hepatotoxicity and the underlying cellular, biochemical and immunological mechanism(s): a critical discussion. Environ Toxicol Pharmacol 37(1):118–133
Abboud G, Kaplowitz N (2007) Drug-induced liver injury. Drug Saf 30(4):277–294
Elkiran T, Harputluoglu H, Yasar U, Babaoglu MO, Dincel AK, Altundag K et al (2007) Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients. Methods Find Exp Clin Pharmacol 29(1):27–32
Ethiraj P, Veerappan K, Samuel S, Sivapatham S (2015) Inhibitory effects of interferon-beta on hepatocellular carcinoma HepG2 via Akt/STAT phosphorylation. Fundam Clin Pharmacol 29(3):278–285
Malaguarnera G, Cataudella E, Giordano M, Nunnari G, Chisari G, Malaguarnera M (2012) Toxic hepatitis in occupational exposure to solvents. World J Gastroenterol 18(22):2756–2766
Pedrycz A, Wieczorski M, Czerny K (2004) Increased apoptosis in the adult rat liver after a single dose of adriamycin administration. Ann Univ Mariae Curie Sklodowska Med 59(2):313–318
Fouad AA, Albuali WH, Al-Mulhim AS, Jresat I (2013) Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity. Environ Toxicol Pharmacol 36(2):347–357
El-Sayyad HI, Ismail MF, Shalaby FM, Abou-El-Magd RF, Gaur RL, Fernando A et al (2009) Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int J Biol Sci 5(5):466–473
Henninger C, Huelsenbeck J, Huelsenbeck S, Grosch S, Schad A, Lackner KJ et al (2012) The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. Toxicol Appl Pharmacol 261(1):66–73
Matouk AI, Taye A, Heeba GH, El-Moselhy MA (2013) Quercetin augments the protective effect of losartan against chronic doxorubicin cardiotoxicity in rats. Environ Toxicol Pharmacol 36(2):443–450
Park S, Yoon J, Bae S, Park M, Kang C, Ke Q et al (2014) Therapeutic use of H2O2-responsive anti-oxidant polymer nanoparticles for doxorubicin-induced cardiomyopathy. Biomaterials 35(22):5944–5953
Vyas D, Laput G, Vyas AK (2014) Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco Targets Ther 7:1015–1023
Poli G, Parola M (1997) Oxidative damage and fibrogenesis. Free Radic Biol Med 22(1–2):287–305
Mironova NL, Petrushanko IY, Patutina OA, Sen’kova AV, Simonenko OV, Mitkevich VA et al (2013) Ribonuclease binase inhibits primary tumor growth and metastases via apoptosis induction in tumor cells. Cell Cycle 12(13):2120–2131
Zheng JY, Yang GS, Wang WZ, Li J, Li KZ, Guan WX et al (2005) Overexpression of Bax induces apoptosis and enhances drug sensitivity of hepatocellular cancer-9204 cells. World J Gastroenterol 11(23):3498–3503
Jia Y, Zuo D, Li Z, Liu H, Dai Z, Cai J et al (2014) Astragaloside IV inhibits doxorubicin-induced cardiomyocyte apoptosis mediated by mitochondrial apoptotic pathway via activating the PI3K/Akt pathway. Chem Pharm Bull (Tokyo) 62(1):45–53
Yang F, Chen H, Liu Y, Yin K, Wang Y, Li X et al (2013) Doxorubicin caused apoptosis of mesenchymal stem cells via p38, JNK and p53 pathway. Cell Physiol Biochem 32(4):1072–1082
Katic M, Bosnjak B, Gall-Troselj K, Dikic I, Pavelic K (2006) A clinoptilolite effect on cell media and the consequent effects on tumor cells in vitro. Front Biosci 11:1722–1732
Li D, Li J, An Y, Yang Y, Zhang SQ (2013) Doxorubicin-induced apoptosis in H9c2 cardiomyocytes by NF-kappaB dependent PUMA upregulation. Eur Rev Med Pharmacol Sci 17(17):2323–2329
Pavelic K, Hadzija M, Bedrica L, Pavelic J, Dikic I, Katic M et al (2001) Natural zeolite clinoptilolite: new adjuvant in anticancer therapy. J Mol Med (Berl) 78(12):708–720
Dogliotti G, Malavazos AE, Giacometti S, Solimene U, Fanelli M, Corsi MM et al (2012) Natural zeolites chabazite/phillipsite/analcime increase blood levels of antioxidant enzymes. J Clin Biochem Nutr 50(3):195–198
Saribeyoglu K, Aytac E, Pekmezci S, Saygili S, Uzun H, Ozbay G et al (2011) Effects of clinoptilolite treatment on oxidative stress after partial hepatectomy in rats. Asian J Surg 34(4):153–157
Fabian G, Farago N, Feher LZ, Nagy LI, Kulin S, Kitajka K et al (2011) High-density real-time PCR-based in vivo toxicogenomic screen to predict organ-specific toxicity. Int J Mol Sci 12(9):6116–6134
Acknowledgments
This study was funded by Istanbul Bilim University.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yapislar, H., Taskin, E., Ozdas, S. et al. Counteraction of Apoptotic and Inflammatory Effects of Adriamycin in the Liver Cell Culture by Clinopitolite. Biol Trace Elem Res 170, 373–381 (2016). https://doi.org/10.1007/s12011-015-0476-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12011-015-0476-3