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An Investigation of the MEK/ERK Inhibitor U0126 in Acute Myeloid Leukemia
Author(s) -
KERR A H J.,
JAMES J A.,
SMITH M A.,
WILLSON C,
COURT E L.,
SMITH J G.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1299.013
Subject(s) - mapk/erk pathway , mek inhibitor , myeloid leukemia , acute myeloblastic leukemia , apoptosis , kinase , leukemia , protein kinase a , cancer research , mitogen activated protein kinase , myeloid , cell culture , biology , immunology , microbiology and biotechnology , biochemistry , genetics
A bstract : 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. This investigation examined the effect of the potent MEK/ERK inhibitor U0126 on apoptosis in acute myeloblastic leukemia (AML) cell lines, and acute leukemic and non‐leukemic patient samples. The pro‐apoptotic effect of the inhibitor varied across the five cell lines tested (KG1a, HEL, TF‐1, MO7e, and THP‐1) from highly significant induction of apoptosis to no apparent response. The pro‐apoptotic effect of U0126 in the most sensitive cell line, KG1a, appeared to be related to its CD34 positivity. Three of five leukemic bone marrow samples showed considerable sensitivity to the inhibitor and a similar association with CD34 expression was evident. Interestingly, control marrow cells from six non‐leukemic patients did not show a significant effect when exposed to U0126. These results suggest that this agent may offer a potential alternative to standard chemotherapy with a particular role in the most primitive types of leukemia, these often being the most resistant to standard chemotherapy.