santonin and Leukemia

DAAS is the diacetoxy acetal derivative of a-santonin and induces HL-60 cell differentiation into granulocytes. In this report, we investigated the structure-activity relationship (SAR) of DAAS derivatives in the differentiation of human HL-60 leukemia cells. Although its derivatives themselves had less effect on HL-60 cell differentiation than DAAS, the monoacetyl derivative, 2, mainly induced HL-60 cell differentiation. Moreover, compound 2 synergistically enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation when combined with 50 nM ATRA, a well-known differentiation inducer. This enhancing effect is similar to that of DAAS in ATRA-induced differentiation.

Topics: Antineoplastic Agents; Cell Differentiation; Dose-Response Relationship, Drug; Drug Synergism; HL-60 Cells; Humans; Leukemia; Molecular Structure; Santonin; Structure-Activity Relationship; Tretinoin

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.

Topics: Cell Differentiation; DNA; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Granulocyte Precursor Cells; HL-60 Cells; Humans; Leukemia; Molecular Structure; NF-kappa B; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Kinase C; Santonin