Takahashi N, Fukui T, Iwahori A, Kubo Y, Hosoe T, Kawai K
Faculty of Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan.
Exp Cell Res. 1998 Dec 15;245(2):313-20. doi: 10.1006/excr.1998.4254.
Mer-NF8054X is a new type of steroid whose structure has been established as 11-oxo-18, 22-cycloergosta-6, 8(14)-diene-3beta, 5beta, 9beta, 23S-tetraol (an 18, 22-cycloergostane), which has been reported to have antifungal activity against Aspergillus fumigatus. However, other biological activities are unknown. Herein, we reported that Mer-NF8054X inhibited cell growth of HL60 human leukemia cells, when used either singly or in combination with retinoic acid (RA). In addition, Mer-NF8054X alone induced differentiation and apoptosis of HL60 cells. The induction of differentiation of HL60 cells by Mer-NF8054X was synergistic in combination with RA. On the other hand, Emesterone A, an analogue of Mer-NF8054X which is missing a hydroxy residue from the third position, showed much lower activity than Mer-NF8054X on the inhibition of cell growth and the induction of cell differentiation and apoptosis. However, Emesterone B, an analogue of Emesterone A which is missing a hydroxy residue from the fifth position, showed higher activity than Emesterone A but lower activity than Mer-NF8054X when examined for the inhibition of cell growth and the induction of cell differentiation and apoptosis. These results suggested that Mer-NF8054X and its analogs may be a new type of differentiation inducing agent. The hydroxy residue at the third position or fifth position in Mer-NF8054X may be necessary, but not essential, for inhibition of growth and induction of both differentiation and apoptosis of HL60 cells. In addition, Mer-NF8054X enhanced the differentiation of HL60 cells induced by RA. Based on these results, Mer-NF8054X may have utility in the clinic in combination with RA for leukemia patients.
Mer-NF8054X是一种新型类固醇，其结构已确定为11-氧代-18,22-环麦角甾-6,8(14)-二烯-3β,5β,9β,23S-四醇（一种18,22-环麦角甾烷），据报道它对烟曲霉具有抗真菌活性。然而，其其他生物学活性尚不清楚。在此，我们报道了Mer-NF8054X单独使用或与视黄酸（RA）联合使用时可抑制HL60人白血病细胞的生长。此外，单独使用Mer-NF8054X可诱导HL60细胞分化和凋亡。Mer-NF8054X与RA联合可协同诱导HL60细胞分化。另一方面，Mer-NF8054X的类似物Emesterone A在第三位缺少一个羟基残基，在抑制细胞生长以及诱导细胞分化和凋亡方面的活性远低于Mer-NF8054X。然而，Emesterone A的类似物Emesterone B在第五位缺少一个羟基残基，在检测其对细胞生长的抑制以及细胞分化和凋亡的诱导时，其活性高于Emesterone A但低于Mer-NF8054X。这些结果表明，Mer-NF8054X及其类似物可能是一种新型的分化诱导剂。Mer-NF8054X第三位或第五位的羟基残基对于抑制HL60细胞生长以及诱导其分化和凋亡可能是必要的，但并非不可或缺。此外，Mer-NF8054X增强了RA诱导的HL60细胞分化。基于这些结果，Mer-NF8054X与RA联合应用于白血病患者可能具有临床应用价值。
