Stabilization of Mitochondrial Function by Ellagic Acid Prevents Celecoxib-induced Toxicity in Rat Cardiomyocytes and Isolated Mitochondria

Abstract

The possible action of polyphenolic compounds in the reduction of reactive oxygen species (ROS) and mitochondrial toxicity may suggest them as putative agents for the treatment of drug-induced mitochondrial dysfunction and cardiotoxicity. This study was designed to explore protective effect of ellagic acid (EA) against celecoxib-induced cellular and mitochondrial toxicity in cardiomyocytes and their isolated mitochondria. In order to do this, isolated cardiomyocytes and mitochondria were pretreated with 3 different concentrations of EA (10, 50 and 100 µM), after which celecoxib (16 µg/ml) was added to promote deleterious effects on cells and mitochondria. Using flow cytometry and biochemical methods, the parameters of cellular and mitochondrial toxicity were investigated. Our results showed that celecoxib (16 µg/ml) caused a significant decrease in cell viability, mitochondrial membrane potential (MMP), glutathione (GSH) in intact cardiomyocytes and succinate dehydrogenase (SDH) activity, MMP collapse, and mitochondrial swelling, and a significant increase in reactive oxygen species (ROS) formation, lipid peroxidation (LP) and oxidative stress in isolated mitochondria. Also, our results revealed that co-administration of EA (50 and 100 µM) with celecoxib significantly attenuated the cellular and mitochondrial toxicity effects. In this study, we showed that simultaneous treatment with of EA ameliorated the cellular and mitochondrial toxicity induced by celecoxib, with cardiomyocytes presenting normal activity compared to the control group, and mitochondria retaining their normal activity.

Key words

celecoxib - ellagic acid - polyphenols - cardiotoxicity - mitochondria

• References

• 1 Mosler C. Cardiovascular risk associated with NSAIDs and COX-2 inhibitors. US Pharm 2014; 39: 35-38
• 2 Caldwell B, Aldington S, Weatherall M. et al. Risk of cardiovascular events and celecoxib: A systematic review and meta-analysis. Journal of the Royal Society of Medicine 2006; 99: 132-140
• 3 Varga Z, Rafay ali Sabzwari S, Vargova V. Cardiovascular risk of nonsteroidal anti-inflammatory drugs: an under-recognized public health issue. Cureus 2017; 9
• 4 Arber N, Eagle CJ, Spicak J. et al. Celecoxib for the prevention of colorectal adenomatous polyps. New England Journal of Medicine 2006; 355: 885-895
• 5 Ghosh R, Alajbegovic A, Gomes AV NSAIDs and cardiovascular diseases: Role of reactive oxygen species. Oxidative Medicine and Cellular Longevity 2015; 2015: 536962. doi: 10.1155/2015/536962
• 6 Lal N, Kumar J, Erdahl WE. et al. Differential effects of non-steroidal anti-inflammatory drugs on mitochondrial dysfunction during oxidative stress. Archives of Biochemistry and Biophysics 2009; 490: 1-8
• 7 Salimi A, Neshat MR, Naserzadeh P. et al. Mitochondrial permeability transition pore sealing agents and antioxidants protect oxidative stress and mitochondrial dysfunction induced by naproxen, diclofenac and celecoxib. Drug Research 2019; 69: 598-605
• 8 Shabalala S, Muller C, Louw J. et al. Polyphenols, autophagy and doxorubicin-induced cardiotoxicity. Life Sciences 2017; 180: 160-170
• 9 Saso L, Firuzi O. Pharmacological applications of antioxidants: lights and shadows. Current Drug Targets 2014; 15: 1177-1199
• 10 Shakeri A, Zirak MR, Sahebkar A. Ellagic acid: a logical lead for drug development?. Current Pharmaceutical Design 2018; 24: 106-122
• 11 Ríos J-L, Giner RM, Marín M. et al. A pharmacological update of ellagic acid. Planta Medica 2018; 84: 1068-1093
• 12 Firdaus F, Zafeer MF, Anis E. et al. Ellagic acid attenuates arsenic induced neuro-inflammation and mitochondrial dysfunction associated apoptosis. Toxicology Reports 2018; 5: 411-417
• 13 Mohammad Khanlou E, Atashbar S, Kahrizi F. et al. Bevacizumab as a monoclonal antibody inhibits mitochondrial complex II in isolated rat heart mitochondria: ameliorative effect of ellagic acid. Drug and Chemical Toxicology 2020; 1-8
• 14 Nippert F, Schreckenberg R, Schlüter K-D. Isolation and cultivation of adult rat cardiomyocytes. JoVE (Journal of Visualized Experiments) 2017; e56634
• 15 Naserzadeh P, Mehr SN, Sadabadi Z. et al. Curcumin protects mitochondria and cardiomyocytes from oxidative damage and apoptosis induced by hemiscorpius lepturus venom. Drug Research 2018; 68: 113-120
• 16 Salimi A, Roudkenar MH, Sadeghi L. et al. Selective anticancer activity of acacetin against chronic lymphocytic leukemia using both in vivo and in vitro methods: key role of oxidative stress and cancerous mitochondria. Nutrition and Cancer 2016; 68: 1404-1416
• 17 Hissin PJ, Hilf R. A fluorometric method for determination of oxidized and reduced glutathione in tissues. Analytical Biochemistry 1976; 74: 214-226
• 18 Huang L, Zhang K, Guo Y. et al. Honokiol protects against doxorubicin cardiotoxicity via improving mitochondrial function in mouse hearts. Scientific Reports 2017; 7: 1-12
• 19 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 1976; 72: 248-254
• 20 Hosseini M-J, Naserzadeh P, Salimi A. et al. Toxicity of cigarette smoke on isolated lung, heart, and brain mitochondria: induction of oxidative stress and cytochrome c release. Toxicological & Environmental Chemistry 2013; 95: 1624-1637
• 21 Salimi A, Roudkenar MH, Seydi E. et al. Chrysin as an anti-cancer agent exerts selective toxicity by directly inhibiting mitochondrial complex II and V in CLL B-lymphocytes. Cancer Investigation 2017; 35: 174-186
• 22 Escobales N, Nuñez RE, Jang S. et al. Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats. Journal of Molecular and Cellular Cardiology 2014; 77: 136-146
• 23 Beach DC, Giroux E. Inhibition of lipid peroxidation promoted by iron (III) and ascorbate. Archives of Biochemistry and Biophysics 1992; 297: 258-264
• 24 Bonora M, Wieckowski MR, Sinclair DA. et al. Targeting mitochondria for cardiovascular disorders: therapeutic potential and obstacles. Nature Reviews. Cardiology 2019; 16: 33-55
• 25 Bonora M, Pinton P. The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Frontiers in Oncology 2014; 4: 302
• 26 Montaigne D, Hurt C, Neviere R Mitochondria death/survival signaling pathways in cardiotoxicity induced by anthracyclines and anticancer-targeted therapies. Biochemistry Research International 2012; 2012
• 27 Tatematsu Y, Fujita H, Hayashi H. et al. Effects of the nonsteroidal anti-inflammatory drug celecoxib on mitochondrial function. Biological and Pharmaceutical Bulletin 2018; 41: 319-325
• 28 Varga ZV, Ferdinandy P, Liaudet L. et al. Drug-induced mitochondrial dysfunction and cardiotoxicity. American Journal of Physiology-Heart and Circulatory Physiology 2015; 309: H1453-H1467
• 29 Davis RE, Williams M. Mitochondrial function and dysfunction: an update. Journal of Pharmacology and Experimental Therapeutics 2012; 342: 598-607
• 30 Camara AK, Bienengraeber M, Stowe DF. Mitochondrial approaches to protect against cardiac ischemia and reperfusion injury. Frontiers in physiology 2011; 2: 13
• 31 Galluzzi L, Kepp O, Trojel-Hansen C. et al. Mitochondrial control of cellular life, stress, and death. Circulation Research 2012; 111: 1198-1207
• 32 Siasos G, Tsigkou V, Kosmopoulos M. et al. Mitochondria and cardiovascular diseases—from pathophysiology to treatment. Annals of translational Medicine 2018; 6
• 33 Kokkou E, Siasos G, Georgiopoulos G. et al. The impact of dietary flavonoid supplementation on smoking-induced inflammatory process and fibrinolytic impairment. Atherosclerosis 2016; 251: 266-272
• 34 Siasos G, Tousoulis D, Tsigkou V. et al. Flavonoids in atherosclerosis: an overview of their mechanisms of action. Current Medicinal Chemistry 2013; 20: 2641-2660
• 35 Larrosa M, García-Conesa MT, Espín JC. et al. Ellagitannins, ellagic acid and vascular health. Molecular Aspects of Medicine 2010; 31: 513-539
• 36 Lin M-c, Yin M-c. Preventive effects of ellagic acid against doxorubicin-induced cardio-toxicity in mice. Cardiovascular Toxicology 2013; 13: 185-193
• 37 Warpe VS, Mali VR, Arulmozhi S. et al. Cardioprotective effect of ellagic acid on doxorubicin induced cardiotoxicity in wistar rats. Journal of Acute Medicine 2015; 5: 1-8
• 38 Dhingra R, Dhingra A, Jayas R. et al. Polyphenolic-Ellagic Acid Suppresses Mitophagy-Induced Necrotic Cell Death During Doxorubicin Cardiotoxicity. Circulation Research 2015; 117: A25-A25
• 39 Hemmati A, Olapour S, Varzi HN. et al. Ellagic acid protects against arsenic trioxide–induced cardiotoxicity in rat. Human & Experimental Toxicology 2018; 37: 412-419
• 40 Dhingra A, Jayas R, Afshar P. et al. Ellagic acid antagonizes Bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes. Free Radical Biology and Medicine 2017; 112: 411-422
• 41 Ebrahimi R, Sepand MR, Seyednejad SA. et al. Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats. DARU. Journal of Pharmaceutical Sciences 2019; 27: 721-733