Journal of Bioenergetics and Biomembranes

, Volume 38, Issue 1, pp 11–21 | Cite as

Preferential Energy- and Potential-Dependent Accumulation of Cisplatin–Gutathione Complexes in Human Cancer Cell Lines (GLC4 and K562): A Likely Role of Mitochondria

  • Simplice Dzamitika
  • Milena Salerno
  • Elene Pereira-Maia
  • Laurence Le Moyec
  • Arlette Garnier-Suillerot


cis-Diamminedichloroplatinum(II) (CDDP) is an important chemotherapeutic agent used in the treatment of a wide variety of solid tumors. We have recently shown that aquated forms of cisplatin (aqua-Pt) rapidly accumulate in K562 and GLC4 cultured cells, in comparison to CDDP. Thus, when cells are incubated with aquated forms of cisplatin a gradient of concentration is observed after a short time, approximately 40 min, with an intracellular concentration of aqua-Pt of 20–30 times higher than that of extracellular aqua-Pt. The same gradient of concentration is observed when cells are incubated with CDDP but it takes a longer time, i.e., about 24 h. Therefore, the question arises as to the identity of the intracellular sites of accumulation of aqua-Pt. Using several agents to modulate membrane potential, acidic compartment pH and/or ATP level, we obtained evidence that aqua-Pt may accumulate rapidly inside mitochondria as this accumulation is energy- and membrane-potential-dependent. However, aqua-Pt complexes are not characterized by a delocalized charge and a lipophilic character that would permit their movement through the inner membrane. Therefore, it is suggested that intracellular aqua-Pt reacts rapidly with glutathione with the resultant complex being transported inside the mitochondria via one of the known glutathione transporters, i.e., dicarboxylate and/or 2-oxoglutarate transporters present in the inner membrane.


Cisplatin Mitochondria Glutathione Accumulation 



cis-diammine-dichloro-platinum(II) or cisplatin










once deprotonated glutathione


mitochondrial glutathione




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  1. Anania F, Potter J, Rennie-Tankersley L, et al (1996) Arch Biochem Biophys 331:1640–1648 CrossRefGoogle Scholar
  2. Basolo F, and Pearson R G (1967) In Mechanisms of Inorganic Reactions, Wiley, New York, pp 351–453Google Scholar
  3. Berghmans K, Ruiz-Cabello J, Simpkins J, et al (1992) Biochem Biophys Res Commun 183:114–120CrossRefPubMedGoogle Scholar
  4. Berners-Price S J, Barnham K J, Frey U, et al (1996) Chem Eur J 2:1283–1291CrossRefGoogle Scholar
  5. Berners-Price S J, and Kuchel P W (1990) J Inorg Biochem 38:327–345CrossRefPubMedGoogle Scholar
  6. Bose R N, Ghosh S K, and Moghaddas S (1997) J Inorg Biochem 65:199–205CrossRefPubMedGoogle Scholar
  7. Brenner J, Magrill E B, Sordillo P P, et al (1982) Cancer 50:2031–2033PubMedCrossRefGoogle Scholar
  8. Chen Z, and Lash L H (1998) J Pharm Exp Ther 285:608–618Google Scholar
  9. Chen Z, Putt D A, and Lash L H (2000) Arch Biochem Biophys 373:193–202CrossRefPubMedGoogle Scholar
  10. Dabrowiak J C, Goodisman J, and Souid A-K (2002) Drug Metabol Disposit 30:1378–1384CrossRefGoogle Scholar
  11. Drose S, Bindseil K U, Siebers E J, et al (1993) Biochemistry 32:3902–3906CrossRefPubMedGoogle Scholar
  12. Dwyer P J O, Stevenson J P, and Johnson S W (1999) In Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug (Lippert, B, ed), VHCA, Basel, Switzerland, pp 31–69Google Scholar
  13. Fernandez-Checa J C, and Kaplowitz N (2005) Toxicol Appl Pharmacol 204:263–273CrossRefPubMedGoogle Scholar
  14. Giurgiovich A J, Diwan B A, Olivero O A, et al (1997) Carcinogeneisis 18:93–96CrossRefGoogle Scholar
  15. Hagrman D, Goodisman J, and Souid A-K (2004) J Pharmacol Exp Ther 308:658–666CrossRefPubMedGoogle Scholar
  16. Huang H, Zhu L, Reid B R, et al (1995)Science 270:1842–1845PubMedCrossRefGoogle Scholar
  17. Jamieson E R, and Lippard S J (1999) Chem Rev 99:2467–2498CrossRefPubMedGoogle Scholar
  18. Jiang S, Song M J, Shin E C, et al (1999) Hepatology 29:101–110CrossRefPubMedGoogle Scholar
  19. Kruidering M, Van de Water B, De Heer E, et al (1997) J Pharmacol Exp Ther 280:638–649PubMedGoogle Scholar
  20. Leibbrandt M E I, Wolfgang G H I, Metz A L, et al (1995) Kidney Int 48:761–770PubMedCrossRefGoogle Scholar
  21. Lieberthal W, Triaca V, and Levine J (1996) Am J Physiol (Renal Fluid Electrolyte Physiol) 270:F700–F708Google Scholar
  22. Lim M C, and Martin B (1976) J Inorg Nucl Chem 38:1191–1914Google Scholar
  23. Lluis J M, Colell A, Garcia-Ruiz C, et al (2003) Gastroenterology 124:708–724CrossRefPubMedGoogle Scholar
  24. Loetchutinat C, Priebe W, and Garnier-Suillerot A (2001) Eur J Biochem 268:4459–4467CrossRefPubMedGoogle Scholar
  25. Loetchutinat C, Saengkhae C, Marbeuf-Gueye C, et al (2003) Eur J Biochem 270:476–485CrossRefPubMedGoogle Scholar
  26. Lozzio C B, and Lozzio B B (1975) Blood 45:321–334PubMedGoogle Scholar
  27. Martensson J, Lai J C, and Meister A (1990) Proc Natl Acad Sci USA 87:7185–7189PubMedCrossRefGoogle Scholar
  28. Miao K, Potter J, Anania F A, et al (1997) Arch Biochem Biophys 341:140–152CrossRefPubMedGoogle Scholar
  29. Miller S E, and House D A (1991) Inorg Chim Acta 187:125–137CrossRefGoogle Scholar
  30. Okuda M, Masaki K, Fukatsu S, et al (2000) Biochem Pharmacol 59:195–201CrossRefPubMedGoogle Scholar
  31. Olivero O A, Semino C, Kassim A, et al (1995) Mutat Res Lett 346:221–230CrossRefGoogle Scholar
  32. Park M S, De Leon M, and Devarajan P J (2002) Am Soc Nephrol 13:858–865CrossRefGoogle Scholar
  33. Pereira-Maia E, and Garnier-Suillerot A (2003) J Biol Inorg Chem 8:626–634CrossRefPubMedGoogle Scholar
  34. Piwnica-Worms D, Jacob R, and Lieberman M (1985) J Gen Physiol 85:43–64CrossRefPubMedGoogle Scholar
  35. Rawlings C J, and Roberts J J (1986) Mutat Res 166:157–169PubMedGoogle Scholar
  36. Roberts J J, Knox R J, Friedlos F, et al (1986) In Biochemical Mechanisms of Platinum Antitumor Drugs (Mc Brien, C H, and Slater, T F, eds), IRL Press, Oxford, pp 29–64 Google Scholar
  37. Rosen M, Figliomeni M, and Simpkins H (1992) {Int J Exp Pathol} {73}:61–74PubMedGoogle Scholar
  38. Rosencweig M, Van Hoff D D, Slavik M, et al (1977) Ann Intern Med 86:803–812 PubMedGoogle Scholar
  39. Saengkhae C, Loetchutinat C, and Garnier-Suillerot A (2003) Biophys J 85:2006–2014PubMedGoogle Scholar
  40. Sharma R P, and Edwards I R (1983) Biochem Pharmacol 32:2665–2669CrossRefPubMedGoogle Scholar
  41. Strandberg M, Bresnick E, and Eastman A (1982) Chem Biol Interact 39:169–180CrossRefPubMedGoogle Scholar
  42. Ueda N, Kaushal G P, and Shah S V (2000) Am J Med 108:403–415CrossRefPubMedGoogle Scholar
  43. Van de Water B, Tijdens I B, Verbrugge A, et al (2000) J Biol Chem 33:25805–25813CrossRefGoogle Scholar
  44. Vergotte J, Moretti J-L, de Vries E G, et al (1998) Eur J Biochem 252:140–146CrossRefPubMedGoogle Scholar
  45. Volckova E, Dudones L P, and Bose R N (2002) Pharm Res 19:124–131CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC. 2006

Authors and Affiliations

  • Simplice Dzamitika
    • 1
  • Milena Salerno
    • 1
  • Elene Pereira-Maia
    • 2
  • Laurence Le Moyec
    • 1
  • Arlette Garnier-Suillerot
    • 1
  1. 1.Biophysique Moléculaire Cellulaire et Tissulaire (BioMoCeTi UMR-CNRS 7033)Université Paris 13 et Université Paris 6, UFR SMBHBobignyFrance
  2. 2.Departamento de Quimica – ICExUniversidade Federal de Minas GeraisBelo HorizonteBrazil

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