Effect of propolis on pyruvate kinase and superoxide dismutase activities in doxorubicin–induced tissue damage: Molecular docking analysis

• Seval Yilmaz Firat University, Faculty of Veterinary Medicine, Department of Biochemistry. Elazig, Türkiye
• Emre Kaya Firat University, Faculty of Veterinary Medicine, Department of Biochemistry. Elazig, Türkiye
• Harun Yonar Selcuk University, Faculty of Veterinary Medicine, Deparment of Biostatistics. Konya, Türkiye
• Harun Uslu Firat University, Faculty of Pharmacy, Department of Pharmaceutical Professional Sciences, Department of Pharmaceutical Chemistry. Elazig, Türkiye

DOI: https://doi.org/10.52973/rcfcv-e34311

Keywords: Doxorubicin, toxicity, pyruvate kinase, superoxide dismutase, molecular docking

Abstract

This study aimed to investigate the effect of propolis on pyruvate kinase (PK) which is a key enzyme in glycolysis and superoxide dismutase (SOD), an antioxidant enzyme on toxicity induced by DOX in different tissues. Using molecular docking, It was looked into how propolis affected the enzymes responsible for glycolysis and the antioxidant system. There was no application in the first group (control). The second group received 100 mg·kg^-1 day of propolis by gavage needle for 7 days, a single dose of 20 mg·kg^-1 intraperitoneal DOX to the third group, and propolis+DOX to the fourth group. Two days prior to DOX administration, propolis application began, and it lasted for seven days. PK and SOD activities were determined in liver, heart, kidney, and testis tissues, and molecular docking was applied to ratify the activity of some propolis components (caffeic acid phenethyl ester (CAPE) and Quercetin) on PK and SOD enzymes. When the DOX group was compared with the control group, a decrease in PK and SOD activities were found, and significant difference was found in PK and SOD activities. Administration of DOX decreased PK and SOD activities of liver, heart, kidney, and testis tissues. In conclusion, our study reveals that DOX disrupts glycolysis in rat tissues. CAPE and Quercetin compounds were shown to interact similarly with the cocrystal ligands of PK and SOD. In addition, when the interaction types of these compounds especially on PK and the docking scores obtained were examined, it can be said that they show higher affinity than DOX.

References

Eleiwa NZ, Galal AA, El–Aziz A, Reda M, Hussin EM. Antioxidant activity of Spirulina platensis alleviates doxorubicin–induced oxidative stress and reprotoxicity in male rats. Oriental Pharm. Exp. Med. [Internet]. 2018; 18(2):87–95. doi: https://doi.org/mjdx

Yang W, Lu Z. Pyruvate kinase M2 at a glance. J. Cell Sci. [Internet]. 2015; 128(9):1655–1660. doi: https://doi.org/f7ck3d

Warburg O. On the origin of cancer cells. Sci. [Internet]. 1956; 123(3191):309–314. doi: https://doi.org/fj737q

Wu SF, Le HY. Dual roles of PKM2 in cancer metabolism. Acta Biochim. Biophys. Sin. [Internet]. 2013; 45(1):27–35. doi: https://doi.org/f4kndk

Mazurek S, Boschek CB, Hugo F, Eigenbrodt E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. [Internet]. 2005; 15(4):300–308. doi: https://doi.org/bpg6sb

Abdel–Daim MM, Kilany O, Khalifa HA, Ahmed AA. Allicin ameliorates doxorubicin–induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer chem. Pharmacol. [Internet]. 2017; 80(4):745–753. doi: https://doi.org/gbzxnw

Sarvazyan NA, Askari A, Huang WH. Effects of doxorubicin on cardiomyocytes with reduced level of superoxide dismutase. Life Sci. [Internet]. 1995; 57(10):1003–1010. doi: https://doi.org/bhgvdr

Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. [Internet]. 2003; 17(10):1195–1214. doi: https://doi.org/brndsj

Fialkow L, Wang Y, Downey GP. Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Rad. Biol. Med. [Internet]. 2007; 42(2):153–164. doi: https://doi.org/fnx4d8

Raj S, Franco VI, Lipshultz SE. Anthracycline–induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment. Curr. Treat. Opt. Cardio. Med. [Internet]. 2014; 16(6):1–14. doi: https://doi.org/mjd6

Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin–induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol. [Internet]. 2012; 52(6):1213–1225. doi: https://doi.org/f3xjqt

Renu K, Sruthy KB, Parthiban S, Sugunapriyadharshini S, George A, Tirupathi–Pichiah TB, Suman S, Abilash V G, Arunachalam S. Elevated lipolysis in adipose tissue by doxorubicin via PPARα activation associated with hepatic steatosis and insulin resistance. Eur. J. Pharmacol. [Internet]. 2019; 843:162–176. doi: https://doi.org/mjd7

Arunachalam S, Tirupathi–Pichiah PB, Achiraman S. Doxorubicin treatment inhibits PPARγ and may induce lipotoxicity by mimicking a type 2 diabetes–like condition in rodent models. FEBS Lett. [Internet]. 2013; 587(2):105–110. doi: https://doi.org/f4h3vh

Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ. Res. [Internet]. 2013; 113(6):709–724. doi: https://doi.org/f5nxvg

Van Raamsdonk JM, Hekimi S. Reactive oxygen species and aging in Caenorhabditis elegans: causal or casual relationship? Antioxid. Redox Sig. [Internet]. 2010; 13(12):1911–1953. doi: https://doi.org/cwg6wb

Mohan UP, Kunjiappan S, Tirupathi–Pichiah PB, Arunachalam S. Adriamycin inhibits glycolysis through downregulation of key enzymes in Saccharomyces cerevisiae. Biotech. [Internet]. 2021; 11(1):1–13. doi: https://doi.org/mjd8

Ciaccio M, Valenza M, Tesoriere L, Bongiorno A, Albiero R, Livrea MA. Vitamin A inhibits doxorubicin–induced membrane lipid peroxidation in rat tissues in vivo. Arc. Biochem. Biophy. [Internet]. 1993; 302(1):103–108. doi: https://doi.org/cprnh6

Mohamed EK, Osman AA, Moghazy AM, Rahman A, As A. Propolis protective effects against doxorubicin–ınduced multi–organ toxicity via suppression of oxidative stress, inflammation, apoptosis, and histopathological alterations in female albino rats. Biointerface Res. Appl. Chem. [Internet]. 2021; 12:1762–1777. doi: https://doi.org/mjd9

Sameni HR, Ramhormozi P, Bandegi AR, Taherian AA, Mirmohammadkhani M, Safari M. Effects of ethanol extract of propolis on histopathological changes and anti‐oxidant defense of kidney in a rat model for type 1 diabetes mellitus. J. Diabetes Invest. [Internet]. 2016; 7(4):506–513. doi: https://doi.org/f9hhpz

Kaya E, Yılmaz S, Ceribasi S. Protective role of propolis on low and high dose furan–induced hepatotoxicity and oxidative stress in rats. J. Vet. Res. [Internet]. 2019; 63(3):423–431. doi https://doi.org/mhzs

Rivero–Cruz JF, Granados–Pineda J, Pedraza–Chaverri J, Pérez–Rojas JM, Kumar–Passari A, Diaz–Ruiz G, Rivero–Cruz BE. Phytochemical constituents, antioxidant, cytotoxic, and antimicrobial activities of the ethanolic extract of Mexican brown propolis. Antioxid. [Internet]. 2020; 9(1):70. doi: https://doi.org/gp63pm

Ripari N, Sartori AA, da Silva–Honorio M, Conte FL, Tasca KI, Santiago KB, Sforcin JM. Propolis antiviral and immunomodulatory activity: a review and perspectives for COVID–19 treatment. J. Pharm. Pharmacol. [Internet]. 2021; 73(3):281–299. doi: https://doi.org/mjfd

Yilmaz S, Kandemir FM, Kaya E, Ozkaraca M. Chemoprotective effects of propolis on aflatoxin b1–induced hepatotoxicity in rats: Oxidative damage and hepatotoxicity by modulating TP53, oxidative stress. Curr. Prot. [Internet]. 2020; 17(3):191–199. doi: https://doi.org/mh2j

Lee YJ, Liao PH, Chen WK, Yang CC. Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral cancer cells. Cancer Lett. [Internet]. 2000; 153(1–2):51–56. doi: https://doi.org/cgsk64

Erlund I. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nut. Res. [Internet]. 2004; 24(10):851–874. doi: https://doi.org/b5twkq

McConkey BJ, Sobolev V, Edelman M. The performance of current methods in ligand–protein docking. Curr. Sci. [Internet]. 2002 [cited 20 July 2023]; 83(7):845–856. Available in: https://goo.su/MnXD

Ristivojević P, Dimkić I, Guzelmeric E, Trifković J, Knežević M, Berić T, Yesilada E, Milojković–Opsenica D, Stanković S. Profiling of Turkish propolis subtypes: Comparative evaluation of their phytochemical compositions, antioxidant and antimicrobial activities. LWT. [Internet]. 2018; 95:367–379. doi: https://doi.org/mjfj

Yamauchi C, Fujita S, Obara T, Ueda T. Effects of room temperature on reproduction, body and organ weights, food and water intake, and hematology in rats. Lab. Anim. Sci. [Internet]. 1981; 31(3):251–258. doi: https://doi.org/mjfk

Iqbal M, Dubey K, Anwer T, Ashish A, Pillai KK. Protective effects of telmisartan against acute doxorubicin–induced cardiotoxicity in rats. Pharmacol. Rep. [Internet]. 2008 [cited 20 July 2023]; 60(3):382–390. Available in: https://goo.su/KkQ6u. Cited in: PubMed; PMID 18622063.

Kaya E, Yılmaz S. Determination of effects of Nigella sativa oil on doxorubicin–ınduced cardiotoxicity in rats. Firat Uni. Vet. J. Health Sci. [Internet]. 2019 [cited 15 July; 2023]; 33(1):31–36. Available in: https://goo.su/l5vOqN. Turkish

Beutler E, Blume KG, Kaplan JC, Löhr GW, Ramot B, Valentine WN. International Committee for Standardization in Haematology: Recommended methods for red‐cell enzyme analysis. British J. Haematol. [Internet]. 1977; 35(2):331–340. doi: https://doi.org/csvd2s

Sun YI, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin. Chem. [Internet]. 1988; 34(3):497–500. doi: https://doi.org/gj74fn

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J. Biol. Chem. [Internet]. 1951; 193(1):265–275. doi: https://doi.org/ghv6nr

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comp. Chem. [Internet]. 2009; 30(16):2785–2791. doi: https://doi.org/dvtqjs

Jurica MS, Mesecar A, Heath PJ, Shi W, Nowak T, Stoddard BL. The allosteric regulation of pyruvate kinase by fructose–1, 6–bisphosphate. Structure [Internet]. 1998; 6(2):195–210. doi: https://doi.org/dwzzwc

Renu K, Abilash VG, PB TP, Arunachalam S. Molecular mechanism of doxorubicin–induced cardiomyopathy–An update. Eur. J. Pharmacol. [Internet]. 2018; 818:241–253. doi: https://doi.org/gcrvs2

Damiani RM, Moura DJ, Viau CM, Caceres RA, Henriques JAP, Saffi J. Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Arch. Toxicol. [Internet]. 2016; 90(9):2063–2076. doi: https://doi.org/grcdr2

Lommi J, Koskinen P, Näveri H, Härkönen M, Kupari M. Heart failure ketosis. J. Int. Med. [Internet]. 1997; 242(3):231–238. doi: https://doi.org/c86nj7

Wilson RB, Solass W, Archid R, Weinreich FJ, Königsrainer A, Reymond MA. Resistance to anoikis in transcoelomic shedding: The role of glycolytic enzymes. Pleura Perit. [Internet]. 2019; 4(1): 20190003. doi: https://doi.org/ghfxw6

Israelsen WJ, Vander–Heiden MG. Pyruvate kinase: Function, regulation and role in cancer. Semin. Cell Dev. Biol. [Internet]. 2015; 43:43–51. doi: https://doi.org/f7zc9s

Van den Brink J, Canelas AB, Van Gulik WM, Pronk JT, Heijnen JJ, De Winde JH, Daran–Lapujade P. Dynamics of glycolytic regulation during adaptation of Saccharomyces cerevisiae to fermentative metabolism. App. Env. Microbiol. [Internet]. 2008; 74(18):5710–5723. doi: https://doi.org/brgs4b

Taymaz–Nikerel H, Karabekmez ME, Eraslan S, Kırdar B. Doxorubicin induces an extensive transcriptional and metabolic rewiring in yeast cells. Sci. Rep. [Internet]. 2018; 8(1):1–14. doi: https://doi.org/gd58qk

Pan C, Wang X, Shi K, Zheng Y, Li J, Chen Y, Jin L, Pan Z. MiR–122 reverses the doxorubicin–resistance in hepatocellular carcinoma cells through regulating the tumor metabolism. PloS One [Internet]. 2016; 11(5):e0152090. doi: https://doi.org/f9v9mn

Abdel–aleem S, El–Merzabani MM, Sayed–Ahmed M, Taylor DA, Lowe JE. Acute and chronic effects of adriamycin on fatty acid oxidation in isolated cardiac myocytes. J. Mol. Cell. Cardiol. [Internet]. 1997; 29(2):789–797. doi: https://doi.org/bddkkd

Goffart S, von Kleist–Retzow JC, Wiesner RJ. Regulation of mitochondrial proliferation in the heart: power–plant failure contributes to cardiac failure in hypertrophy. Cardio. Res. [Internet]. 2004; 64(2):198–207. doi: https://doi.org/cq5wbz

Rizk SM, Zaki HF, Mina MA. Propolis attenuates doxorubicin–induced testicular toxicity in rats. Food Chem. Toxicol. [Internet]. 2014; 67:176–186. doi: https://doi.org/f53g96

Orak N, Gakmuk G, Kaya S. An evaluation of damages caused by doxorubicin in liver tissue and potential protective effect of propolis on these damages. Konuralp Med. J. [Internet]. 2022; 14(1):104–113. doi: https://doi.org/mjfr

Perry JJP, Shin DS, Getzoff ED, Tainer JA. The structural biochemistry of the superoxide dismutases. Biochim. Biophys. Acta – Proteins Proteom. [Internet]. 2010; 1804(2):245–262. doi: https://doi.org/fc4wd6

Doroshow JH, Akman S, Chu FF, Esworthy S. Role of the glutathione–glutathione peroxidase cycle in the cytotoxicity of the anticancer quinones. Pharmacol. Therap. [Internet]. 1990; 47(3):359–370. doi: https://doi.org/fmbwrd

Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J. [Internet]. 1990; 4(13):3076–3086. doi: https://doi.org/mjfs

Nitiss JL. DNA topoisomerase II and its growing repertoire of biological functions. Nature Rev. Canc. [Internet]. 2009; 9(5):327–337. doi: https://doi.org/ctfdqc

Cheung KG, Cole LK, Xiang B, Chen K, Ma X, Myal Y, Hatch GM, Tong Q, Dolinsky VW. Sirtuin–3 (SIRT3) protein attenuates doxorubicin–induced oxidative stress and improves mitochondrial respiration in H9c2 cardiomyocytes. J. Biol. Chem. [Internet]. 2015; 290(17):10981–10993. doi: https://doi.org/f69bnn

Kostrzewa–Nowak D, Paine MJI, Wolf CR, Tarasiuk J. The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60–sensitive cell line and its multidrug–resistant sublines. British J. Canc. [Internet]. 2005; 93(1):89–97. doi: https://doi.org/c9fcdw

Swamy AV, Wangikar U, Koti BC, Thippeswamy AHM, Ronad PM, Manjula DV. Cardioprotective effect of ascorbic acid on doxorubicin–induced myocardial toxicity in rats. Indian J. Pharmacol. [Internet]. 2011; 43(5): 507–511. doi: https://doi.org/c8v99c

Rohde LE, Belló–Klein A, Pereira RP, Mazzotti NG, Geib G, Weber C, Clausell N. Superoxide dismutase activity in adriamycin–induced cardiotoxicity in humans: a potential novel tool for risk stratification. J. Card. Fail. [Internet]. 2005; 11(3):220–226. doi: https://doi.org/dt5c96

Köse E, Oğuz F, Vardi N, Sarihan ME, Beytur A, Yücel A, Eki̇nci̇ N. Therapeutic and protective effects of montelukast against doxorubicin–induced acute kidney damage in rats. Iranian J. Basic Med. Sci. [Internet]. 2019; 22(4):407–411. doi: https://doi.org/mjft

Kuropatnicki AK, Szliszka E, Krol W. Historical aspects of propolis research in modern times. Evidence–Based comp. Alt. Med. [Internet]. 2013; (Spec No):964149. doi: https://doi.org/gbc5ft

Cornara L, Biagi M, Xiao J, Burlando B. Therapeutic properties of bioactive compounds from different honeybee products. Front. Pharmacol. [Internet]. 2017; 8(412)1–20. doi: https://doi.org/mjfw

Huang S, Zhang CP, Wang K, Li GQ, Hu FL. Recent advances in the chemical composition of propolis. Molec. [Internet]. 2014; 19(12):19610–19632. doi: https://doi.org/f6vfn2

Burdock GA. Review of the biological properties and toxicity of bee propolis (propolis). Food Chem. Toxicol. [Internet]. 1998; 36(4):347–363. doi: https://doi.org/d2t9t4

Sforcin JM, Bankova, V. Propolis: is there a potential for the development of new drugs? J. Ethnopharmacol. [Internet]. 2011; 133(2):253–260. doi: https://doi.org/fnqzwd

Sheibani M, Nezamoleslami, S, Faghir–Ghanesefat H, Dehpour AR. Cardioprotective effects of dapsone against doxorubicin–induced cardiotoxicity in rats. Canc. Chem. Pharmacol. [Internet]. 2020; 85(3):563–571. doi: https://doi.org/grb2cm

Aksu EH, Kandemir FM, Yıldırım S, Küçükler S, Dörtbudak MB, Çağlayan C, Benzer F. Palliative effect of curcumin on doxorubicin‐induced testicular damage in male rats. J. Biochem. Mol. Toxicol. [Internet]. 2019; 33(10):e22384. doi: https://doi.org/mjfx

Liu HX, Li J, Li QX. Therapeutic effect of valsartan against doxorubicin–induced renal toxicity in rats. Iranian J. Basic Med. Sci. [Internet]. 2019; 22(3):251–254. doi: https://doi.org/mjfz

Husna F, Arozal W, Yusuf H, Safarianti S. Protective effect of mangiferin on doxorubicin–induced liver damage in animal model. J. Res. Pharm. [Internet]. 2022; 26(1):44–51. doi: https://doi.org/mjf2

Nagai K, Fukuno S, Oda A, Konishi, H. Protective effects of taurine on doxorubicin–induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anti–Cancer Drugs [Internet]. 2016; 27(1):17–23. doi: https://doi.org/mjf3

Omobowale TO, Oyagbemi AA, Ajufo UE, Adejumobi OA, Ola–Davies OE, Adedapo AA, Yakubu MA. Ameliorative effect of gallic acid in doxorubicin–induced hepatotoxicity in Wistar rats through antioxidant defense system. J. Dietary Supp. [Internet]. 2018; 15(2):183–196. doi: https://doi.org/mjf4

Fuliang HU, Hepburn HR, Xuan H, Chen M, Daya S, Radloff SE. Effects of propolis on blood glucose, blood lipid and free radicals in rats with diabetes mellitus. Pharmacol. Res. [Internet]. 2005; 51(2):147–152. doi: https://doi.org/dfcqmx

Baykara M, Silici S, Özçelik M, Güler O, Erdoğan N, Bilgen M. In vivo nephroprotective efficacy of propolis against contrast–induced nephropathy. Diag. Inter. Radiol. [Internet]. 2015; 21(4):317–321. doi: https://doi.org/gs8p7d

Promsan S, Jaikumkao K, Pongchaidecha A, Chattipakorn N, Chatsudthipong V, Arjinajarn P, Lungkaphin A. Pinocembrin attenuates gentamicin–induced nephrotoxicity in rats. Canadian J. Physiol. Pharmacol. [Internet]. 2016; 94(08):808–818. doi: https://doi.org/f8zkx6