Preferential energy- and potential-dependent accumulation of cisplatin-gutathione complexes in human cancer cell lines (GLC4 and K562): A likely role of mitochondria.
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.
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Biophysique Moléculaire Cellulaire et Tissulaire (BioMoCeTi UMR-CNRS 7033), Université Paris 13 et Université Paris 6, UFR SMBH, 74 rue Marcel Cachin, 93017, Bobigny, France.
Salerno
Milena
M
Pereira-Maia
Elene
E
Le Moyec
Laurence
L
Garnier-Suillerot
Arlette
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001693:Biological Transport, Active; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000493:pharmacokinetics*; D004734:Energy Metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology
D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate; D005978:Glutathione; D002945:Cisplatin