Induction of erythroid differentiation of K562 cells by 4-carbamoylimidazolium 5-olate (SM-108).
The effects of 4-carbamoylimidazolium 5-olate (SM-108), an antipurine compound, on a human leukemia cell line, K562, were studied. Treatment with SM-108 induced erythroid differentiation of K562 cells. During a 6-day culture with 100 microM SM-108, the cell number decreased to 37% of the control number, 77% of the cells became benzidine-positive, and the hemoglobin content increased from 2.1 +/- 0.2 to 10.6 +/- 1.3 pg/cell. Cell differentiation was associated with reduction of IMP dehydrogenase activity and intracellular GTP content to 25 and 36%, respectively, of the control values within 1.5 hr. The differentiation and decrease in the GTP pool induced by SM-108 were blocked by the presence of 25 microM guanine or guanosine. SM-108 also induced erythroid differentiation of K562 subline cells transfected with pMSG (K562/pMSG), which have an additional salvage pathway for GMP production from xanthine. The addition of 100 microM xanthine prevented erythroid differentiation of this subline and restored the GTP pool. These findings suggest that the induction of erythroid differentiation of K562 cells by SM-108 may be due to an early decrease in IMP dehydrogenase activity and a subsequent decrease in GTP content in the cells. Thus, purine metabolism may have an important role in SM-108-induced differentiation.
First Department of Internal Medicine, Kagawa Medical School, Japan.
Y
Y
Hata
Y
Y
Yamaji
T
T
Shiotani
J
J
Fujita
H
H
Kamano
K
K
Ikeda
J
J
Takahara
S
S
Irino
D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D011687:Purines / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D019820:Xanthine; D014970:Xanthines / Q000494:pharmacology
D007093:Imidazoles; D011687:Purines; D014970:Xanthines; D019820:Xanthine; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C033758:4-carbamoylimidazolium 5-olate