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• W1947650470 abstract "4619 A novel sterol mesylate (NSC 67657) was previously identified as a potent activator of CEBPα signaling in an HTS assay, and it was also demonstrated that this compound could induce myeloid differentiation in U937 and HL60 human leukemia cell lines. The present study compared transcription profiles (generated from 20,000K oligonucleotide arrays) of HL60 cells, treated with NSC 67657 (20μM) and all-trans retinoic acid (ATRA, 5μM), which suggested these two agents produced differentiated cells along different lineages. While ATRA induced gene expression changes related to granulocytic differentiation, NSC 67657 triggered monocytic differentiation as evidenced by prominent induction of CD14 and other related genes. Additional data supporting NSC 67657 induction of monocyte/macrophage differentiation was generated using flow cytometry and the NBT test in HL60 and NB4 (acute promyelocytic leukemia) cells. Both cells lines were induced to differentiate (>99% of the cells) following 2μM ATRA treatment for 5-7 days measured by reduction of nitroblue tetrazolium to its insoluble formazan (NBT assay), and >90% of the cells expressed CD18 and CD35, but not CD14. In contrast only HL60 cells were induced to differentiate (NBT assay) following NSC67675 treatment and 95% of the cells were positive for expression of CD14. However, NB4 cells (which only terminally differentiate into monocytes/macrophages in the presence of phorbol esters), showed no indication of differentiating either by the NBT assay or markers of differentiation following treatment with NSC 67657. When HL60 cells were implanted intraperitoneally into athymic mice, and treated orally beginning on day 3, with 200mg/kg NSC 67657 bid qd x 5, and ascites cells extracted on day 7, these cells were found to express elevated levels of the CD14 mRNA (>20fold), or antigen as measured by flow cytometry. Thus the sterol mesylate agent, NSC 67657, which activates CEBPα signaling, has been shown to primarily initiate monocytes/macrophage differentiation as opposed to granulocytic differentiation in HL60 cells, both in vitro and in vivo. These results indicate that NSC 67657 is a novel differentiating agent that warrants further preclinical evaluation as a potential anti-leukemic drug. Supported by NCI contract # NO1-CO-12400." @default.
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• W1947650470 date "2006-04-15" @default.
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• W1947650470 title "A sterol mesylate activator of CEBPα signaling induces monocytic differentiation in human leukemia cells in vitro and in vivo" @default.
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