Since differentiation-induction
therapy represents an attractive strategy for treatment of a wide range of
malignancies, universal efforts have been devoted to find new and potent differentiation inducers devoid of general toxicities. In that respect,
3-hydrogenkwadaphnin (3-HK), a novel
daphnane-type
diterpene ester from Dendrostellera lessertii (Thymelaeaceae), was found to be an effective inducer of megakaryocytic differentiation in
chronic myelogenous leukemia (CML) K562 cells without any adverse effects on normal cells [Moosavi, M.A., Yazdanparast, R., Sanati, M.H., Nejad, A.S., 2005.
3-Hydrogenkwadaphnin targets
inosine 5'-monophosphate
dehydrogenase and triggers post-G1 arrest apoptosis in human
leukemia cell lines. International Journal of Biochemistry and Cell Biology 37, 2366-2379]. In this study, we found that inhibition of cellular replication and maturation, induced by the
drug, are dependent upon ERK/MAPK activation. Inhibition of
MEK activity by
PD98059 reversed the growth arrest, decreased adhesive properties, induction of polyploidization and blocked the expression of GPIIb
integrin, induced by 3-HK. Immunoblot analyses also showed that 3-HK-induced sustained activation of ERK1/2 from early exposure times, before the onset of differentiation, up to 96 h. Moreover, our results revealed that
cyclin D1 and p21(Cip/WAF1) were increased during differentiation. Consequently, it is concluded that up-regulation of
cyclin D1, accompanied by the persistent activation of ERK/MAPK, is involved in the megakaryocytic differentiation of K562 cells under the influence of 3-HK.