Pharmacological inhibitors of extracellular signal-regulated protein kinases attenuate the apoptotic action of cisplatin in human myeloid leukemia cells via glutathione-independent reduction in intracellular drug accumulation.
It has been reported that inhibition of extracellular signal-regulated protein kinases (ERKs) attenuates the toxicity cisplatin (cis-platinum (II)-diammine dichloride) in some cell types. This response was here investigated using human myeloid leukemia cells. Cisplatin stimulated ERK1/2 phosphorylation and caused apoptosis in U-937 promonocytic cells, an effect which was attenuated by the MEK/ERK inhibitors PD98059 and U0126. While ERK1/2 activation was a general phenomenon, irrespective of the used cell type or antitumour drug, the MEK/ERK inhibitors only reduced cisplatin toxicity in human myeloid cells (THP-1, HL-60 and NB-4), but not in RAW 264.7 mouse macrophages and NRK-52E rat renal tubular cells; and failed to reduce the toxicity etoposide, camptothecin, melphalan and arsenic trioxide, in U-937 cells. U0126 attenuated cisplatin-DNA binding and intracellular peroxide accumulation, which are important regulators of cisplatin toxicity. Although cisplatin decreased the intracellular glutathione (GSH) content, which was restored by U0126, treatments with GSH-ethyl ester and dl-buthionine-(S,R)-sulfoximine revealed that GSH does not regulate cisplatin toxicity in the present experimental conditions. In spite of it, PD98059 and U0126 reduced the intracellular accumulation of cisplatin. These results suggest that GSH-independent modulation of drug transport is a major mechanism explaining the anti-apoptotic action of MEK/ERK inhibitors in cisplatin-treated myeloid cells.
Amrán
Donna
D
Centro de Investigaciones Biológicas, CSIC. Ramiro de Maeztu 9, 28040-Madrid, Spain.
Sancho
Patricia
P
Fernández
Carlos
C
Esteban
Diego
D
Ramos
Adrián M
AM
de Blas
Elena
E
Gómez
Milagros
M
Palacios
María A
MA
Aller
Patricio
P
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid; D051379:Mice; D009336:Necrosis; D010084:Oxidation-Reduction; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D000975:Antioxidants; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D002083:Butylated Hydroxyanisole; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione; D002945:Cisplatin