Chemical modification of santonin into a diacetoxy acetal form confers the ability to induce differentiation of human promyelocytic leukemia cells via the down-regulation of NF-kappaB DNA binding activity.
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.
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701.
Seung Hyun
SH
Kim
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757.
Ju Han
JH
Song
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757.
Bo Gil
BG
Choi
Genome Research Center for Hematopoietic Diseases, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea.
Hyeoung-Joon
HJ
Kim
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701; Genome Research Center for Hematopoietic Diseases, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea. Electronic address: tskim@korea.ac.kr.
Tae Sung
TS
Kim
D002454:Cell Differentiation / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D042381:Granulocyte Precursor Cells / Q000187:drug effects* / Q000473:pathology; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D012500:Santonin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*
C511609:3,3-(ethylenedioxy)-eudesmano-13,6-diacetate; D016328:NF-kappa B; D012500:Santonin; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases