Differential regulation of antioxidant enzymes by resveratrol in healthy and cancerous hepatocytes

Year 2022, , 62 - 68, 15.11.2022

Aykut Bostancı , Esma Nur Şencan , Ayşegül Kütük , Gökhan Sadi

https://doi.org/10.30616/ajb.1103463

Abstract

Üzüm, yaban mersini, ahududu, dut ve yer fıstığı gibi bitkilerde bulunan resveratrol, çeşitli patolojik sorunlara karşı koruma sağlayan doğal olarak sentezlenmiş bir polifenoldür. Kanser hücrelerinde oksidatif stresin artışı ve hücresel antioksidan sistemlerin baskılanması belirlenmiş olup, bitkisel antioksidanların çeşitli kanser türlerinin tedavisinde yardımcı madde olarak kullanılabileceği öngörülmektedir. Bu çalışmada, güçlü bir antioksidan olan resveratrolün sağlıklı ve kanserli karaciğer hücrelerinde antioksidan enzimlerin gen ekspresyonu ve aktiviteleri üzerindeki etkileri araştırılmıştır. Karaciğer kanseri hücreleri (HepG2) ve sağlıklı hepatositler (THLE2) resveratrol ile farklı dozlarda (25-, 50-, 75- µM) 48 saat süreyle muamele edildikten sonra antioksidan enzimlerin gen ekspresyon seviyeleri qRT-qPCR ile, aktiviteleri ise spektrofotometrik olarak ölçülmüştür. Sonuçlar, THLE2 hücrelerindeki tüm antioksidan enzimlerin resveratrolün tüm dozlarında baskılandığını, ancak bunun tersine HepG2 hücrelerinde antioksidan enzimlerin yukarı regülasyonunu göstermiştir. Sağlıklı hücrelerde görülen gen ekspresyonundaki azalma, katalaz ve glutatyon S-transferazın enzimatik aktivitelerinin baskılanmasıyla paralel değiştiği, ancak kanser hücresindeki aktivite değişikliklerinin anlamlı olmadığı belirlenmiştir. Sağlıklı ve kanserli hepatositlerde antioksidan enzim sistemlerinin farklı olarak düzenlemesi, kanser hücrelerinde antioksidan enzimlerin oksidatif hasara karşı koruyucu bir işlev olarak uyarılmasını gösterirken, sağlıklı hücrelerde azalmış ekspresyon, tersine antioksidan ihtiyacının azalmasına işaret etmektedir. Bu nedenle resveratrol, kanser hücrelerinde antioksidan enzimleri aktive ederek hücresel stresi azaltabilecek moleküler mekanizmaları etkileyerek kanser tedavisinde etkili olabilir.

Keywords

Resveratrol, antioxidant enzymes, gene expression, oxidative stress

References

• Abdul-Rahman O, Sasvari-Szekely M, Ver A, Rosta K, Szasz BK, Kereszturi E, Keszler G (2012). Altered Gene Expression Profiles in the Hippocampus and Prefrontal Cortex of Type 2 Diabetic Rats. BMC Genomics 13: 81.
• Aebi H (1974). Catalase. In: Bergmeyer HU (ed) Methods of Enzymatic Analysis. Verlag Chemie/Academic Press Inc., Weinheim/NewYork, pp 673–680
• Akbel E, Arslan-Acaroz D, Demirel HH, Kucukkurt I, Ince S (2018). The Subchronic Exposure to Malathion, an Organophosphate Pesticide, Causes Lipid Peroxidation, Oxidative Stress, and Tissue Damage in Rats: The Protective Role of Resveratrol. Toxicol Res (Camb) 7: 503–512.
• Alves A de F, Moura AC de, Andreolla HF, da Veiga ABG, Fiegenbaum M, Giovenardi M, de Almeida S (2021). Gene Expression Evaluation of Antioxidant Enzymes in Patients with Hepatocellular Carcinoma: RT-QPCR and Bioinformatic Analyses. Genet Mol Biol 44: 20190373.
• Athar M, Back J, Tang X, Kim K, Kopelovich L, Bickers D, Kim A (2007). Resveratrol: A Review of Preclinical Studies for Human Cancer Prevention. Toxicol Appl Pharmacol 224: 274–283.
• Berman AY, Motechin RA, Wiesenfeld MY, Holz MK (2017). The Therapeutic Potential of Resveratrol: A Review of Clinical Trials. npj Precis Oncol 1: 1–9.
• Bertelli AAE (2007). Wine, Research and Cardiovascular Disease: Instructions for Use. Atherosclerosis 195: 242–247.
• Catalgol B, Batirel S, Taga Y, Ozer NK (2012). Resveratrol: French Paradox Revisited. Front Pharmacol 3: 1–18.
• Dai T, Li R, Liu C, Liu W, Li T, Chen J, Kharat M, McClements DJ (2019). Effect of Rice Glutelin-Resveratrol Interactions on The Formation and Stability of Emulsions: A Multiphotonic Spectroscopy and Molecular Docking Study. Food Hydrocoll 97: 105234.
• Fitzmaurice C, Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Naghavi M, et al. (2017). The Burden of Primary Liver Cancer and Underlying Etiologies from 1990 to 2015 at the Global, Regional, and National Level Results from the Global Burden of Disease Study 2015. JAMA Oncol 3: 1683–1691.
• Graves DT, Liu R, Alikhani M, Al-Mashat H, Trackman PC (2006). Diabetes-Enhanced Inflammation and Apoptosis--Impact on Periodontal Pathology. J Dent Res 85: 15–21.
• Habig WH, Pabst MJ, Jakoby WB (1974). Glutathione S-Transferases. The First Enzymatic Step in Mercapturic Acid Formation. J Biol Chem 249: 7130–9.
• Karabekir SC, Özgörgülü A (2020). Possible Protective Effects of Resveratrol in Hepatocellular Carcinoma. Iran J Basic Med Sci 23: 71–78.
• Kataria R, Khatkar A (2019). Resveratrol in Various Pockets: A Review. Curr Top Med 19: 116–122.
• Khan MA, Chen HC, Wan XX, Tania M, Xu AH, Chen FZ, Zhang DZ (2013). Regulatory Effects of Resveratrol on Antioxidant Enzymes: A Mechanism of Growth Inhibition and Apoptosis Induction in Cancer Cells. Mol Cells 35: 219–225.
• Khan MA, Tania M, Zhang DZ, Chen HC (2010). Antioxidant Enzymes and Cancer. Chinese J Cancer Res. 22:87–92.
• Klaunig J. (2018). Oxidative Stress and Cancer. Curr Pharm Des 24: 4771–4778.
• Ko JH, Sethi G, Um JY, Shanmugam MK, Arfuso F, Kumar AP, Bishayee A, Ahn KS (2017). The Role of Resveratrol in Cancer Therapy. Int J Mol Sci. 18:2589.
• Liou GY, Storz P (2010). Reactive Oxygen Species in Cancer. Free Radic Res. 44:479–496.
• Liu FC, Tsai HI, Yu HP (2015). Organ-Protective Effects of Red Wine Extract, Resveratrol, in Oxidative Stress-Mediated Reperfusion Injury. Oxid Med Cell Longev. 2015:568634.
• Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951). Protein Measurement with the Folin Phenol Reagent. J Biol Chem 193: 265–75.
• Moloney JN, Cotter TG (2018). ROS Signalling in the Biology of Cancer. Semin. Cell Dev Biol. 80:50–64.
• Ough M, Lewis A, Zhang Y, Hinkhouse MM, Ritchie JM, Oberley LW, Cullen JJ (2004). Inhibition of Cell Growth by Overexpression of Manganese Superoxide Dismutase (MnSOD) in Human Pancreatic Carcinoma. Free Radic Res 38: 1223–1233.
• Sadi G, Kartal DI, Guray T (2013). Regulation of Glutathione S-Transferase Mu with Type 1 Diabetes and Its Regulation with Antioxidants. Turkish J Biochem 38: 92–10.
• Sadi G, Sadi Ö (2010). Antioxidants and Regulation of Antioxidant Enzymes by Cellular Redox Status. Turkish J Sci Rev 3: 95–107.
• Stivala L, Savio M, Carafoli F, Perucca P (2001). Specific Structural Determinants Are Responsible for The Antioxidant Activity and The Cell Cycle Effects of Resveratrol. J Biol Chem 276: 22586–22594.
• Studer A, Curran DP (2016). Catalysis of Radical Reactions: A Radical Chemistry Perspective. Angew Chemie - Int Ed 55: 58–102.
• Tarocchi M, Galli A (2017). Oxidative Stress as a Mechanism for Hepatocellular Carcinoma. In: Liver Pathophysiology: Therapies and Antioxidants. pp 279–287
• Teoh-Fitzgerald MLT, Fitzgerald MP, Jensen TJ, Futscher BW, Domann FE (2012). Genetic and Epigenetic Inactivation of Extracellular Superoxide Dismutase Promotes an Invasive Phenotype in Human Lung Cancer by Disrupting ECM Homeostasis. Mol Cancer Res 10: 40–51.
• Vestergaard M, Ingmer H (2019). Antibacterial and Antifungal Properties of Resveratrol. Int J Antimicrob Agents 53: 716–723.
• Zhang L, Liu Y, Ke Y, Liu Y, Luo X, Li C, Zhang Z, Liu A, Shen L, Chen H, Hu B, Wu H, Wu W, Lin D, Li S (2018). Antidiabetic Activity of Polysaccharides from Suillellus Luridus in Streptozotocin-Induced Diabetic Mice. Int J Biol Macromol 119: 134–140.