Pharmacological inhibition of the MAPK/ERK pathway increases sensitivity to 2-chloro-2'-deoxyadenosine (CdA) in the B-cell leukemia cell line EHEB.
EHEB leukemic cells, which are derived from a patient suffering B-cell chronic lymphocytic leukemia (B-CLL), display intermediate sensitivity to the purine analogue 2-chloro-2'-deoxyadenosine (CdA). Because the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway can rescue cancer cells from apoptotic signals, we investigated MAPK/ERK signaling in EHEB cells in response to CdA. We observed that CdA, at concentrations around its IC50, dose- and time-dependently increased the phosphorylation state of ERK 1/2 (p-ERK), indicating an activation of the MAPK/ERK pathway. This activation required CdA metabolism and de novo protein synthesis, and was independent on caspase activation. Interruption of ERK signaling, using the specific MEK inhibitors U-0126 and PD-98059, significantly enhanced CdA cytotoxicity, evaluated by the MTT assay. Drug interaction analysis showed synergism in the majority of combinations between CdA and MEK inhibitors tested. MEK inhibitors also dramatically increased apoptosis induced by CdA alone, evaluated by caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage. Collectively, these observations show that ERK 1/2 activation elicited by CdA serves as a cytoprotective function and suggest that inhibitors of this pathway could be combined with CdA in the treatment of selected hematological malignancies.
Smal
Caroline
C
Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, B-1200 Brussels, Belgium.
Lisart
Stéphanie
S
Maerevoet
Marie
M
Ferrant
Augustin
A
Bontemps
Françoise
F
Van Den Neste
Eric
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017338:Cladribine / Q000494:pharmacology*; D004347:Drug Interactions; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D017338:Cladribine; D048049:Extracellular Signal-Regulated MAP Kinases