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

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Abstract

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.

Abbreviations

Ac-DEVD-pNA
N-acetyl-Asp-Glu-Val-Asp-p-nitroaniline
BHA
butylated hydroxyanisole
BSO
dl-buthionine-(S,R)-sulfoximine
CDDP
cisplatin, cis-platinum (II)-diammine dichloride
DAPI
4,6-diamino-2-phenylindole
ERK
extracellular signal-regulated kinase
FI-ICP-MS
flow injection-inductively coupled plasma mass spectrometry
GSH
reduced glutathione
GSH-OEt
reduced glutathione ethyl ester
H2DCFDA
dichlorodihydrofluorescein diacetate
JNK
c-Jun NH2-terminal kinase, stress-activated protein kinase 1
MAPK
mitogen-activated protein kinase
PBS
phosphate-buffered saline
PI
propidium iodide
PKC
calcium-dependent protein kinase
TPA
12-O-tetradecanoylphorbol-13-acetate

Keywords

Cisplatin
Apoptosis
ERK inhibitor
Drug accumulation
Glutathione
Myeloid cell

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