Abstract
It has been observed that astrocyte and astrocytoma cells differ in their response to d-ribose-l-cysteine (RibCys) in the culture medium. RibCys, a prodrug of l-cysteine, elevates the level of cysteine and glutathione in both astrocytoma and astrocyte cultures. It also affects the activity of two sulfurtransferases, 3-mercaptopyruvate sulfurtransferase and rhodanese, involved in the metabolism of sulfane sulfur-containing compounds and in consequence exerts an effect on the level of sulfane sulfur. Under conditions, in which the raised level of sulfane sulfur was accompanied by an elevated activity of 3-mercaptopyruvate sulfurtransferase, the proliferation of the human astrocytome U373 line was decreased. The experiments were simultaneously performed with murine astrocytes to compare the behavior of normal cells under similar conditions. In murine astrocytes, RibCys was capable of increasing cellular proliferation, and was accompanied by a diminished level of sulfane sulfur and unchanged activity of the two sulfurtransferases. Thus, RibCys might offer a therapeutic advantage in the inhibition of astrocytoma cell proliferation. Besides, in the absence of oxidative stress, measured as the ratio of GSH/GSSG, the obtained results confirm that the fall in the level of sulfane sulfur is associated with increasing proliferation of cells, whereas a rise in the level causes a decrease in the proliferation of U373 cells.
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References
Arrigo AP (1999) Gene expression and thiol redox state. Free Radic Biol Med 27:936–944
Atzori L, Dypbukt JM, Sundqvist K, Cotgreave I, Edman CC, Moldeus P, Grafstrom RC (1990) Growth-associated modifications of low-molecular-weight thiols and protein sulfhydryls in human bronchial fibroblasts. J Cell Physiol 143:165–171
Dominick PK, Cassidy PB, Roberts JC (2001) A new and versatile method for determination of thiolamines of biological importance. J Chromatogr B 761:1–12
Droge W, Breitkreutz R (2000) Glutathione and immune function. Proc Nutr Soc 59:595–600
Estrela JM, Hernandez R, Terradez P, Asensi M, Puertes RI, Vina J (1992) Regulation of glutathione metabolism in Ehrlich ascites tumor cells. Biochem J 286:257–262
Estrela JM, Ortega A, Obrador E (2006) Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 43(2):143–181
Gardiner CS, Reed DJ (1995) Synthesis of glutathione in the preimplantation mouse embryo. Arch Biochem Biophys 318:30–36
Ghibellia L, Fanellia C, Rotilioa G, Lafaviaa E, Coppolaa S, Colussia C, Civitarealea P, Ciriolob MR (1998) Rescue of cells from apoptosis by inhibition of active GSH extrusion. FASEB J 12:479–486
Guebela DV, Torresb NV (2004) Dynamics of sulfur amino acids in mammalian brain: assessment of the astrocytic-neuronal cysteine interaction by a mathematical hybrid model. Biochim Biophys Acta 1674:12–28
Hall AG (1999a) Glutathione and the regulation of cell death. Adv Exp Med Biol 457:199–203
Hall AG (1999b) The role of glutathione in the regulation of apoptosis. Eur J Clin Invest 29:238–245
Hamilos DL, Zelarney P, Mascali JJ (1989) Lymphocyte proliferation in glutathione-depleted lymphocytes: direct relationship between glutathione availability and the proliferative response. Immunopharmacology 18:223–235
Hwang C, Sinskey AJ (1991) The role of oxidation-reduction potential in monitoring growth of mammalian cultured cells. In: Spier RE, Griffiths JB, Meignier B (eds) Production of biologicals from animal cells in culture. Halley Court, Oxford, pp 548–657
Iwata S, Hori T, Sato N, Ueda-Taniguchi Y, Yamabe T, Nakamura H, Masutani H, Yodoi J (1994) Thiol-mediated redox regulation of lymphocyte proliferation: possible involvement of adult T cell leukemia-derived factor and glutathione in transferring receptor expression. J Immunol 152:5633–5642
Jones DP (2002) Redox potential of GSH/GSSG couple: assay and biological significance. Methods Enzymol 348:93–112
Jurkowska H, Wróbel M (2008) N-acetyl-l-cysteine as a source of sulfane sulfur in astrocytoma and astrocyte cultures: correlations with cell proliferation. Amino Acids 34:231–237. doi:10.1007/s00726-007-0471-2
Kosower EM (1970) A role for glutathione in muscle contraction. Experientia 26:76–77
Lang CA, Mills BJ, Mastropaolo W, Liu MC (2000) Blood glutathione decreases in chronic diseases. J Lab Clin Med 135:402–405
Livingstone C, Davis J (2007) Targeting therapeutics against glutathione depletion in diabetes and its complications. Br J Diabetes Vasc Dis 7:258–265
Lowry OH, Rosenbrough NJ, Farr AL, Randal RI (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
McCarthy KD, de Vellis J (1980) Preparation of separate astroglial and oligodendroglial cell cultures from at cerebral tissue. J Cell Biol 85:890–902
Meister A (1989) Metabolism and function of glutathione. In: Dolphin D, Poulson R, Avramovic O (eds) Glutathione: chemical and biochemical and medical aspects. Wiley, New York, pp 367–474
Mihm S, Galter D, Droge W (1995) Modulation of transcription factor NF-kB activity by intracellular glutathione levels and by variations of the extracellular cysteine supply. FASEB J 9:246–252
Ogasawara Y, Isoda S, Tanabe S (1994) Tissue and subcellular distribution of bound and acid-labile sulfur, and the enzymic capacity for sulfide production in the rat. Biol Pharm Bull 17:1535–1542
Oz HS, Chen TS, Nagasawa H (2007) Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis model. Transl Res 150(2):122–129
Ponten J, Macintyre EH (1968) Long term culture of normal and neoplastic human glia. Acta Pathol Microbiol Scand 74:465–486
Qusti S, Parsons RB, Abouglila KDH, Waring RH, Williams AC, Ramsden DB (2000) Development of in vitro model for cysteine dioxygenase expression in the brain. Cell Biol Toxicol 16:243–255
Roberts JC, Nagasawa HT, Zera RT, Fricke RF, Goon DJW (1987) Prodrugs of l-cysteine as protective agents against acetaminophen-induced hepatotoxicity. 2-(polyhydroxyalkyl)- and 2-(polyacetoxyalkyl)thiazolidine-4(R)-carb oxylic acids. J Med Chem 30:1891–1896
Roberts JC, Koch KE, Detrick SR, Warters RL, Lubec G (1995) Thiazolidine prodrugs of cysteamine and cysteine as radioprotective agents. Radiat Res 143:203–213
Shanker G, Allen JW, Mutkus LA, Aschner M (2001) The uptake of cysteine in cultured primary astrocytes and neurones. Brain Res 902:156–163
Shaw JP, Chou IN (1986) Elevation of intracellular glutathione content associated with mitogenic stimulation of quiescent fibroblasts. J Cell Physiol 129:193–198
Sőrbo B (1955) Rhodanese. Methods Enzymol 2:334–337
Stavrovskaya AA (2000) Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc) 65:95–106
Suthanthiran M, Anderson ME, Sharma VK, Meister A (1990) Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens. Proc Natl Acad Sci USA 87:3343–3347
Szczepkowski TW, Wood JL (1967) The cystathionase-rhodanese system. Biochim Biophys Acta 139:469–478
Terradez P, Asensi M, Lasso delareza MC, Puertes IR, Vina J, Estrela JM (1993) Depletion of tumor glutathione in vivo by buthionine sulfoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth. Biochem J 292:477–483
Toohey JI (1989) Sulphane sulphur in biological systems: a possible regulatory role. Biochem J 264:625–632
Ubuka T, Yuasa S, Ishimoto Y, Shimomura M (1977) Desulfuration of l-cysteine through transamination and transsulfuration in rat liver. Physiol Chem Phys 9:241–246
Ubuka T, Okada A, Nakamura H (2008) Production of hypotaurine from l-cysteinesulfinate by rat liver mitochondria. Amino acids 35(1):53–58
Valentine WN, Frankenfeld JK (1974) 3-Mercaptopyruvate sulfurtransferase (E.C.2.8.1.2): a simple assay adapted to human blood cells. Clin Chim Acta 51:205–210
Westley J, Adler H, Westley L, Nishida C (1983) The sulfurtransferases. Fundam Appl Toxicol 3:377–382
Wood JL (1987) Sulfane sulfur. In: Jakoby WB, Griffith OW (eds) Methods in enzymology, vol 143. Academic Press, San Diego, pp 25–29
Wróbel M, Jurkowska H, Śliwa L, Srebro Z (2004) Sulfurtransferases and cyanide detoxification in mouse liver, kidney and brain. Toxicol Mech Methods 14:331–337
Yoshida K, Hirokawa J, Tagami S, Kawakami Y, Urata Y, Kondo T (1995) Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux. Diabetologia 38:201–210
Zmuda J, Friedenson B (1983) Changes in intracellular glutathione pool levels in stimulated and unstimulated lymphocytes in the presence of 2-mercaptoethanol or cysteine. J Immunol 130:362–364
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This work was supported by a grant from the Polish Committee for Scientific Research (KBN) K/ZDS/000450 and K/ZBW/000147.
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This article is part of the Special Issue on Sulfur- and Seleno-containing Amino Acids.
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Jurkowska, H., Uchacz, T., Roberts, J. et al. Potential therapeutic advantage of ribose-cysteine in the inhibition of astrocytoma cell proliferation. Amino Acids 41, 131–139 (2011). https://doi.org/10.1007/s00726-010-0593-4
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DOI: https://doi.org/10.1007/s00726-010-0593-4