New retinoids inhibiting the growth of human acute promyelocytic leukemia cell line HL-60 without inducing differentiation.
A series of acid homologs with longer side chain length was synthesized and their biological activities to inhibit growth and to induce differentiation of human acute promyelocytic leukemia cell line HL-60 were analyzed. It was found that ethyl alpha-retinylidene propionate (E) shows interesting activity. This compound inhibited growth of HL-60 cells with almost the same potency of retinoic acid. However, unlike retinoic acid, the potency of this compound to induce differentiation of HL-60 cells into neutrophiles was almost negligible. Ethyl alpha-retinylidene propionate (E) is an unprecedented retinoid which inhibits growth of HL-60 cells without inducing cell differentiation. The Z isomer [ethyl alpha-retinylidene propionate (Z)] also showed similar unique effects on HL-60 cells. Interestingly, both of the E and Z isomers of alpha-retinylidene propionic acid showed only very weak activities to inhibit growth and to induce differentiation of HL-60 cells. It was suggested that ethyl alpha-retinylidene propionate acts on HL-60 cells in the intact form without suffering hydrolysis, and also that the ester group plays important role for the unique activity. Biological activities of retinylidene acetic acid (E and Z) which lacks methyl group at alpha-position of alpha-retinylidene propionic acid, on HL-60 cells were weaker than those of the isomers of alpha-retinylidene propionic acid. Esterification of the isomers of retinylidene acetic acid resulted in further decrease of biological activities. Biological activities of ethyl retinoate on HL-60 cells were also very weak. It was indicated that methyl group present at alpha-position of ethyl alpha-retinylidene propionate plays an important role for the unique biological activity. It was further indicated that the effect of esterification of carboxyl group of retinoids on the biological activity is not constant, but varies depending on the structure. Pretreatment of HL-60 cells with ethyl alpha-retinylidene propionate (E) apparently did not influence the process of induction of differentiation of HL-60 cells into neutrophiles by retinoic acid. It was further shown that ethyl alpha-retinylidene propionate (E) prolongs the time necessary for induction of differentiation of HL-60 cells by retinoic acid, but does not influence the level of final rate of differentiation.
Suzuki
T
T
Department of Clinical Genetics, Tokyo Metropolitan Institute of Medical Science, Japan.
Kawamura
S
S
Matsui
M
M
Murayama
A
A
D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D015394:Molecular Structure; D012176:Retinoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D012176:Retinoids