Induction of HL60 cell differentiation by tiazofurin and its analogues: characterization and efficacy

Among inducers of myeloid differentiation for leukemic cells, tiazofurin is of special interest because its mechanism of action is known; it inhibits inosine monophosphate dehydrogenase and thus decreases the guanine nucleotide pool. Reported here are three aspects of tiazofurin induction of myeloid differentiation in HL60 human acute promyelocytic leukemia cells. First, inductive efficacy was evaluated for analogues ara-tiazofurin, xylo-tiazofurin, and selenazofurin, for dinucleotide anabolites thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD), and for a phosphodiesterase-resistant TAD analogue, beta-methylene TAD. The results showed that the parent compounds are more effective inducers than the dinucleotide derivatives and that the selenazole analogues are more effective inducers than the thiazole compounds. Second, HL60 cell induction by tiazofurin was shown to be synergistic with that produced by the antiviral agent ribavirin. Finally, tiazofurin was found to induce expression of a phosphatidylinositol-specific phospholipase C- sensitive Fc gamma-receptor III (FcRIII) on HL60 cells, a feature consistent with neutrophilic, but not monocytic, differentiation.