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J. Biol. Chem., Vol. 281, Issue 19, 13117-13125, May 12, 2006

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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-B DNA Binding Activity^*

Seung Hyun Kim, Ju Han Song, Bo Gil Choi, Hyeoung-Joon Kim^¶, and Tae Sung Kim^¶1

From the School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, the College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, and the ^¶Genome Research Center for Hematopoietic Diseases, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea

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-B 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-B 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.

Received for publication, October 6, 2005 , and in revised form, March 7, 2006.

^* This work was supported by Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea Grant 01-PJ10-PG6-01GN16-0005. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea. Tel.: 82-2-3920-3416; Fax: 82-2-3290-3921; E-mail: tskim{at}korea.ac.kr.

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