An investigation of the effects of the MEK inhibitor U0126 on apoptosis in acute leukemia.
Blockade of mitogen-activated protein kinase kinase (MEK1/2), part of the extracellular signal-regulated kinase (ERK) or p44/42 mitogen-activated protein kinase (MAPK) pathway has been shown, in some instances, to cause apoptosis in leukemic blast cells. However, studies are contradictory and have often been based mainly on inhibition of cell growth in a limited number of cell lines. This investigation examined the effect of the potent MEK inhibitor U0126 alone and in combination with Ara-C on apoptosis in acute myeloblastic leukemia (AML) cell lines, patient acute leukemic and nonleukemic samples. Apoptosis was assessed flow cytometrically using Apo2.7 and AnnexinV antibodies which detect apoptosis at the mitochondrial and cell membrane levels, respectively. The proapoptotic effect of the inhibitor varied across the five cell lines tested, from highly significant induction of apoptosis to no apparent response. A possible synergistic effect with the combined use of U0126 and Ara-C was observed in one cell line only. The proapoptotic effect of U0126 in the most sensitive cell line appeared to be related to CD34 positivity. Cells from leukemic patients showed considerable sensitivity in two of four cases with a similar association with CD34 expression being evident. Interestingly, control cells did not show a significant effect when exposed to the inhibitor. These results suggest that U0126 may offer a potential alternative to standard chemotherapy with a particular role in the most primitive types of leukemia, these being often the most resistant to standard chemotherapy.
James
Jacqueline A
JA
Centre for Research in Biomedicine, Faculty of Applied Sciences, University of West of England, Bristol, UK.
Smith
Margaret Ann
MA
Court
Emma L
EL
Yip
Christina
C
Ching
Yew
Y
Willson
Celia
C
Smith
John Graham
JG
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007938:Leukemia / Q000145:classification / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases