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.

Retinoid Differentiation Therapy for Common Types of Acute Myeloid Leukemia

“…A fall in IMPDH activity was not observed in a retinoid-insensitive variant of the RDFD2-25 cell line, which suggests that the fall in IMPDH activity is an important aspect of the differentiation process. Commensurate with this finding is that depletion of intracellular GTP levels via the use of a variety of IMPDH inhibitors, such as mycophenolate mofetil, tiazofurin and 3-hydrogenkwadaphnin, leads to differentiation and/or apoptosis of myeloid leukemic cell lines [ 92 – 94 ]. Also, treatment of HL-60 and NB4 cells with a combination of ATRA and an IMPDH inhibitor resulted in a greater degree of neutrophil differentiation, followed by apoptosis, than when either agent was used alone [ 95 , 96 ].…”

Inhibitors of the IMPDH Enzyme as Potential Anti-Bovine Viral Diarrhoea Virus Agents

“…The IMPDH K i data in Table 1 were obtained from the literature (Pankiewicz et al, 2002) or references therein. Full compound characterization and degree of purity for all tested compounds have been published previously (Goldstein et al, 1991;Zatorski et al, 1995;Lesiak et al, 1997Lesiak et al, , 1998Pankiewicz et al, 2002).…”

ChemInform Abstract: 2,4‐Disubstituted Thiazoles. Part 3. Synthesis and Antitumor Activity of Ethyl 2‐Substituted‐aminothiazole‐4‐carboxylate Analogues.

“…The antitumor activity of certain 2,4-disubstituted-thiazole analogs was reported recently [1][2][3][4][5] . The demonstrated clinically effective antitumor activity of the thiazole nucleoside tiazofurn [6,7] , the reported facts about the groove binding property of distamycin [8] , netropsin (A), thia-netropsin (B) [9,10] , and the thiazole containing antitumor agent bleomycin [11,12] , prompted us to continue the earlier investigations carried out in our laboratory [13][14][15][16][17][18][19][20][21][22][23] , in the hope of discovering a more active antineoplastic agent.…”