The in vitro effect of 5-FU and Tamoxifen Chemotherapeutics on penthose phosphate pathway enzymes

Year 2021, Volume: 42 Issue: 2, 245 - 251, 30.06.2021

Yusuf Temel

https://doi.org/10.17776/csj.806343

Abstract

The pentose phosphate pathway is the metabolic pathway where NADPH, the reducing force in metabolism, and ribose 5-phosphate, the building block of DNA and RNA, are produced. In this study, the in vitro effects of 5-fluorouracil and Tamoxifen chemotherapeutic agents on glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), which are key enzymes of the pentose phosphate pathway, were investigated. In the first stage of the study, G6PD and 6PGD enzymes were purified from rat erythrocytes using 2ʹ, 5ʹ-ADP Sepharose-4B affinity chromatography. The control of enzyme activities was determined spectrophotometrically at 340 nm wavelength according to the Beutler method. Then, the in vitro effects of 5-FU and Tamoxifen agents, which are widely used in chemotherapy, on enzyme activities were investigated. The results of the study showed that 5-FU increased the activity of both G6PD and 6PGD enzymes in the concentration range of 0.19-1.9 mM and Tamoxifen in the concentration range of 26-260 µM.

Keywords

G6PD, 6PGD, 5-FU, tamoxifen, enzyme, rat erythrocyt

References

• [1] Kasala E.R., Bodduluru L.N., Madana R.M., Athira K. V., Gogoi R., Barua C.C., Chemopreventive and therapeutic potential of chrysin in cancer: Mechanistic perspectives, Toxicol. Lett., 233 (2015) 214–225.
• [2] Buerge I.J., Buser H.R., Poiger T., Müller M.D. Occurrence and fate of the cytostatic drugs cyclophosphamide and ifosfamide in wastewater and surface waters, Environ. Sci. Technol., 40 (2006) 7242–7250.
• [3] Kandemir F.M., Kucukler S., Caglayan C., Gur C., Batil A.A., Gülçin İ. Therapeutic effects of silymarin and naringin on methotrexate-induced nephrotoxicity in rats: Biochemical evaluation of anti-inflammatory, antiapoptotic, and antiautophagic properties, J. Food Biochem., 41 (2017) e12398.
• [4] Temel Y., Kucukler S., Yıldırım S., Caglayan C., Kandemir F.M. Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis, Naunyn. Schmiedebergs. Arch. Pharmacol., 393 (2020) 325–337.
• [5] Caglayan C., Temel Y., Kandemir F.M., Yildirim S., Kucukler S., Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage, Environ. Sci. Pollut. Res., 25(21) (2018) 20968-20984.
• [6] Aybek H., Temel Y., Ahmed B.M., Ağca C.A., Çiftci M. Deciphering of The Effect of Chemotherapeutic Agents on Human Glutathione S-Transferase Enzyme and MCF-7 Cell Line, Protein Pept. Lett., 27 (2020) 1–7.
• [7] Karaman M., Temel, Y., Bayindir S. Inhibition effect of rhodanines containing benzene moieties on pentose phosphate pathway enzymes and molecular docking, J. Mol. Struct., 1220 (2020) 128700.
• [8] Maxwell P.J., Longley D.B., Latif T., Boyer J. Allen W., Lynch M., McDermott U., Paul Harkin, D. Allegra C.J., Johnston P.G. Identification of 5-fluorouracil-inducible target genes using cDNA microarray profiling, Cancer Res., 63 (2003) 4602–4606.
• [9] Glazer R.I., Lloyd L.S. Association of cell lethality with incorporation of 5-fluorouracil and 5-fluorouridine into nuclear RNA in human colon carcinoma cells in culture, Mol. Pharmacol., 21 (1982) 468–473.
• [10] Cohen P., Rosemeyer M.A. Glucose-6-phosphate dehydrogenase from human erythrocytes, Methods Enzymol., 41 (1975) 208–214.
• [11] Pullarkat S.T., Lenz H.J. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy, Pharmacogenomics J., 1 (2001) 65–70.
• [12] Jahani M., Azadbakht M., Norooznezhad F., Mansouri K. L-arginine alters the effect of 5-fluorouracil on breast cancer cells in favor of apoptosis, Biomed. Pharmacother., 88 (2017) 114–123.
• [13] Buckley M.M.T., Goa K.L., Tamoxifen: A Reappraisal of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Use, Drugs, 37 (1989) 451–490. [14] Novick A.M., Scott A.T., Neill Epperson C., Schneck C.D., Neuropsychiatric effects of tamoxifen: Challenges and opportunities, Front. Neuroendocrinol., 59 (2020) 100869. [15] Özmen İ., Çiftçi M., Küfrevioğlu Ö.İ., Çürük M.A., Investigation of glucose 6-phosphate dehydrogenase (G6PD) kinetics for normal and G6PD-deficient persons and the effects of some drugs, J. Enzyme Inhib. Med. Chem., 19 (2004) 45–50.
• [16] Temel Y., Kocyigit U.M., Purification of glucose-6-phosphate dehydrogenase from rat ( Rattus norvegicus ) erythrocytes and inhibition effects of some metal ions on enzyme activity, J Biochem Mol Toxicol. , (2017).
• [17] Adem S., Ciftci M., Purification of rat kidney glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and glutathione reductase enzymes using 2???,5???-ADP Sepharose 4B affinity in a single chromatography step, Protein Expr. Purif., 81 (2012) 1–4.
• [18] Yang X., Peng X., Huang J., Inhibiting 6 ‑ phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation, Clin. Transl. Oncol., 20 (2018) 1145–1152.
• [19] Özaslan M.S., Balcı N., Demir Y., Gürbüz M., Küfrevioğlu Ö.İ., Inhibition effects of some antidepressant drugs on pentose phosphate pathway enzymes, Environ. Toxicol. Pharmacol., 72 (2019).
• [20] Patra K.C., Hay N., The pentose phosphate pathway and cancer, Trends Biochem. Sci., 39 (2014) 347–354.
• [21] Temel Y., Taysi M.Ş., The Effect of Mercury Chloride and Boric Acid on Rat Erythrocyte Enzymes, Biol. Trace Elem. Res., (2018) 177–182.
• [22] Temel Y., Koçyigit U.M., Taysi M.S., Gökalp F., Gürdere M.B., Budak Y., Ceylan M., Gülçin I., Çiftci M., Purification of glutathione S-transferase enzyme from quail liver tissue and inhibition effects of (3aR,4S,7R,7aS)-2-(4-((E)-3-(aryl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives on the enzyme activity, J. Biochem. Mol. Toxicol., 32(3) (2018) e22034.
• [23] Chen H., Wu D., Bao L., Yin T., Lei D., Yu J., Tong X., 6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming, Biomed. Pharmacother., 111 (2019) 1353–1358.
• [24] Temel Y., Kufrevioǧlu Ö.I., Çiftci M., Investigation of the effects of purification and characterization of turkey (Meleagris gallopavo) liver mitochondrial thioredoxin reductase enzyme and some metal ions on enzyme activity, Turkish J. Chem., 41 (2017) 1603-1635.
• [25] Bayindir S., Ayna A., Temel Y., Çiftci M., The synthesis of new oxindoles as analogs of natural product 3,3′-bis(indolyl)oxindole and in vitro evaluation of the enzyme activity of G6PD and 6PGD, Turkish J. Chem., 42 (2018)1706-1751.
• [26] Beydemir S., Gülçin I., Küfrevioğlu O.I., Ciftçi M., Glucose 6-phosphate dehydrogenase: in vitro and in vivo effects of dantrolene sodium., Pol. J. Pharmacol., 55 (2003) 787–792.
• [27] Shewach D.S., Kuchta R.D., Introduction to cancer chemotherapeutics, Chem. Rev., 109 (2009) 2859–2861. [28] Kern J.C., Kehrer J.P., Acrolein-induced cell death: A caspase-influenced decision between apoptosis and oncosis/necrosis, Chem. Biol. Interact., 139 (2002) 79–95.
• [29] Gamelin B.E., Gue V., Delva R., Lortholary A., Genevieve F., Larra F., Ifrah N., Robert J., Correlation between Uracil and Dihydrouracil Plasma Ratio, Fluorouracil (5-FU) Pharmacokinetic Parameters and Tolerance with Advanced Colorectal C, J Clin Oncol., 17(4) (1999) 1105–1110.
• [30] Ashford A.R., Donev I., Tiwari R.P., Garrett T.J., Reversible ocular toxicity related to tamoxifen therapy, Cancer, 61 (1988) 33–35.
• [31] Akkemik E., Budak H., Ciftci M., Effects of some drugs on human erythrocyte glucose 6-phosphate dehydrogenase : an in vitro study, J Enzyme Inhib Med Chem., 25(6) (2010) 871–875.
• [32] Akkoyun H.T. Bengu A.S., Ulucan A., Bayramoglu Akkoyun M., Ekin S., Temel Y., Çiftçi M. Effect Of Astaxanthin On Rat Brains Against Oxidative Stress Induced By Cadmium:Biochemical, Histopathological Evaluation, J. Inst. Sci. Technol., 8 (2018) 33–39.
• [33] Özmen I., Küfrevioǧlu Ö.I., Effects of antiemetic drugs on glucose 6-phosphate dehydrogenase and some antioxidant enzymes, Pharmacol. Res., 50 (2004) 499–504.
• [34] Temel Y., Ayna A., Hamdi Shafeeq I., Ciftci M., In vitro effects of some antibiotics on glucose-6-phosphate dehydrogenase from rat ( Rattus norvegicus ) erythrocyte , Drug Chem. Toxicol., 43(2) (2018) 219-223.
• [35] Adem S., Ciftci M., Purification of rat kidney glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and glutathione reductase enzymes using 2???,5???-ADP Sepharose 4B affinity in a single chromatography step, Protein Expr. Purif., 81 (2012) 1–4.
• [36] Mykkanen H. M., Ganther H. E., Effect of mercuty on erythrocytes glutathione reductase activity: in vivo and in vitro studies., J. Clin. Invest., 48 (1969) 1957–1966.
• [37] Gumustekin K., Ciftci M., Coban A., Altikat S., Aktas O., Gul M., Timur H., Dane S., Effects of nicotine and vitamin E on glucose 6-phosphate dehydrogenase activity in some rat tissues in vivo and in vitro, J. Enzyme Inhib. Med. Chem., 20 (2005) 497–502.
• [38] Temel Y., Bengü A.Ş., Akkoyun H.T., Akkoyun M., Ciftci M., Effect of astaxanthin and aluminum chloride on erythrocyte G6PD and 6PGD enzyme activities in vivo and on erythrocyte G6PD in vitro in rats, J. Biochem. Mol. Toxicol., (2017).
• [39] Bayramoğlu Akkoyun M., Bengü A.Ş., Temel Y., Akkoyun H.T., Ekin S., Ciftci M., The effect of astaxanthin and cadmium on rat erythrocyte G6PD, 6PGD, GR, and TrxR enzymes activities in vivo and on rat erythrocyte 6PGD enzyme activity in vitro, J. Biochem. Mol. Toxicol., 32 (2018) 1–5.
• [40] Petreni A., Bonardi A., Lomelino C., Osman S.M., ALOthman Z.A., Eldehna W.M., El-Haggar R., McKenna R., Nocentini A., Supuran C.T., Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells, Eur. J. Med. Chem., 190 (2020) 112112.
• [41] Nuwaysir E.F., Dragan Y.P., Jefcoate C.R., Jordan,V.C., Pitot H.C., Effects of Tamoxifen Administration on the Expression of Xenobiotic Metabolizing Enzymes in Rat Liver, Cancer Res., 55 (1995) 1780–1786.