Many
sesquiterpene lactone compounds either induce or enhance the cell differentiation of human
leukemia cells. However, we reported in a previous study that
santonin, a
eudesmanolide sesquiterpene lactone, exerts no effects on the differentiation of
leukemia cells. In this report, to evaluate the possibility of chemically modifying
santonin into its derivatives with differentiation inducing activity, we synthesized a series of
santonin derivatives, and determined their effects on cellular differentiation in the human promyelocytic
leukemia HL-60 cell system. A diacetoxy
acetal derivative of
santonin (DAAS) was found to induce significant HL-60 cell differentiation in a dose-dependent manner, whereas
santonin in its original form did not. The HL-60 cells were differentiated into a granulocytic lineage when exposed to DAAS. In addition, the observed induction in cell differentiation closely correlated with the levels of
NF-kappaB DNA binding activity inhibited by DAAS. Both Western blot analyses and
kinase inhibitor studies determined that
protein kinase C, ERK, and
phosphatidylinositol 3-kinase were upstream components of the DAAS-mediated inhibition of
NF-kappaB binding activity in HL-60
leukemia cells. The results of this study indicate that
santonin can, indeed, be chemically modified into a derivative with differentiation inducing abilities, and suggest that DAAS might prove useful in the treatment of neoplastic diseases.