Effects of tiazofurin on globin and proto-oncogene expression in K562 erythroleukemia cells.
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193) is a synthetic nucleoside inhibitor of inosine monophosphate dehydrogenase. This agent has recently been shown to induce differentiation of human leukemia cell lines. In the present study, we have monitored the effects of tiazofurin on differentiation and proto-oncogene expression in K562 erythroleukemia cells. Tiazofurin induced K562 cell hemoglobin production in a concentration-dependent manner. This induction of a differentiated phenotype was also associated with a loss of proliferative capacity. In contrast to the reversible effects of hemin on induction of K562 cell hemoglobin synthesis, the effects of tiazofurin were irreversible. Northern blot analysis of K562 cells treated with 10 microM tiazofurin demonstrated the accumulation of alpha- and gamma-globin mRNA. The results also demonstrate that there was little if any effect of tiazofurin on levels of c-myc, c-myb, or c-abl mRNA. Furthermore, there were no detectable changes in Ki-ras, Ha-ras or N-ras expression at the mRNA and protein levels in tiazofurin-treated K562 cells. These findings suggest that tiazofurin induces changes in levels of globin transcripts but has little if any effect on c-myc, c-myb, c-abl, or c-ras gene expression in K562 cells.
Kharbanda
S M
SM
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
Miyazaki
K
K
Takeyama
H
H
Sherman
M L
ML
Spriggs
D R
DR
Carney
W P
WP
Kufe
D W
DW
D000199:Actins / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects*; D005796:Genes / Q000187:drug effects*; D005914:Globins / Q000235:genetics*; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000187:drug effects*; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000199:Actins; D000970:Antineoplastic Agents; D006454:Hemoglobins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012263:Ribonucleosides; D012254:Ribavirin; D005914:Globins; C033706:tiazofurin