Pyridinyl imidazole inhibitor SB203580 activates p44/42 mitogen-activated protein kinase and induces the differentiation of human myeloid leukemia cells

Abstract 

Various inhibitors of protein kinases regulate the growth and differentiation of human leukemic cell lines. The pyridinyl imidazole inhibitor SB203580 has been widely used to elucidate the role of p38 kinase in a wide array of biological systems. In the present investigation, we found that SB203580 effectively induced the granulocytic differentiation of human promyelocytic HL-60 cells. In addition to morphological differentiation, it also induced NBT-reduction, lysozyme activity and growth-inhibition. It also induced the differentiation of human myeloid leukemia HT93 and ML-1 cells, but not of other cell lines, such as NB4, U937, THP-1, K562 and HEL. This differentiation was not associated with the inhibition of p38 kinase activity, but was closely associated with the activation of extracellular signal-regulated kinase. These results demonstrate a new activity for this drug.

Keywords:  Differentiation, Leukemia cells, Kinase inhibitor, SB203580, Mitogen-activated protein kinase, P38 kinase, Erk2

Abbreviations:  ATRA, all-trans retinoic acid, ActD, actinomycin D, APL, acute promyelocytic leukemia, VD3, 1α,25-dihydroxyvitamin D₃, AraA, 9-β-d-arabinofuranosyladenine, dAd, 2′-deoxyadenosine, ERK, extracellular signal-regulated kinase, MAPK, mitogen-activated protein kinase, MEK, MAPK kinase, NBT, nitroblue tetrazolium