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

Abstract

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.

Synthesis of Nonhydrolyzable Analogues of Thiazole-4-carboxamide and Benzamide Adenine Dinucleotide Containing Fluorine Atom at the C2‘ of Adenine Nucleoside: Induction of K562 Differentiation and Inosine Monophosphate Dehydrogenase Inhibitory Activity

“…Although IMPDH inhibition by TAD and β-CH 2 -TAD is similar, the β-methylene analogue is a less potent inhibitor of growth and inducer of differentiation. This has been attributed to the requirement of 3 to be transported intact across the cell membrane . In contrast, extracellular TAD can be hydrolyzed to the corresponding nucleosides and TF transported readily across the membrane to be reanabolized to the active TAD.…”

“…Recently, we developed a new procedure for DCC-catalyzed coupling of nucleoside 5‘-methylenebis(phosphonate)s with nucleosides, sugars, and alcohols , P 4 -dinucleoside- P 1 : P , P : P -bismethylene tetraphosphonate analogue (Np 4 N) such as 19 . Np 4 A analogues were further dehydrated by the action of DCC forming active bicyclic trisanhydride intermediates 11 such as 19a .…”

“…3 Tiazofurin (1, TF) and its active metabolite TAD (2), as well as the nonhydrolyzable, methylenebis(phosphonate) analogue β-CH 2 -TAD (3), were found to be potent inducers of HL-60 cell differentiation. 4 Analogue 3 was most effective in TFresistant leukemias. Although, 2 and 3 bind to IMPDH with K i s 4 orders of magnitude lower than that of TF, concentrations of 2 and 3 1-1.5 orders of magnitude higher than that of TF are needed to induce a similar level of differentiation in HL-60 cells.…”

“…The known IMPDH inhibitors, such as tiazofurin and mycophenolic acid, induce differentiation in a variety of human leukemia cells, including HL-60 myeloid leukemia cells and K562 erythroid leukemia cells, as well as human breast cancer cells and melanoma cells . Tiazofurin ( 1 , TF) and its active metabolite TAD ( 2 ), as well as the nonhydrolyzable, methylenebis(phosphonate) analogue β-CH 2 -TAD ( 3 ), were found to be potent inducers of HL-60 cell differentiation . Analogue 3 was most effective in TF-resistant leukemias.…”

“…Although, 2 and 3 bind to IMPDH with K i s 4 orders of magnitude lower than that of TF, concentrations of 2 and 3 1−1.5 orders of magnitude higher than that of TF are needed to induce a similar level of differentiation in HL-60 cells. This has been attributed to less efficient cell membrane penetration by the dinucleotides 2 and 3 as well to the hydrolytic instability of pyrophosphates 2 …”