Induction of differentiation and apoptosis in human promyelocytic leukemia HL60 cell line by a new type of steroids.
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.
Takahashi
N
N
Faculty of Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan. t-noriko@hoshi.ac.jp
Fukui
T
T
Iwahori
A
A
Kubo
Y
Y
Hosoe
T
T
Kawai
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001203:Ascomycota; D001230:Aspergillus; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017313:Fenretinide / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007664:Ketosteroids / Q000494:pharmacology / Q000627:therapeutic use; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology; D008264:Macrophages / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D007664:Ketosteroids; C116495:emesterone A; C116496:emesterone B; C088540:Mer NF8054X; D017313:Fenretinide; D014212:Tretinoin; D004247:DNA