Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells

K. Pillwein, K. Schuchter, G. Ressmann, K. Gharenbaghi, A. Knoflach, B. Cermak, H. N. Jayaram, S. M. Szalay, T. Szekeres, P. Chiba

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12 Citations (Scopus)

Abstract

The IMP dehydrogenase inhibitor, tiazofurin (TR)-2-β-D-ribofuranosylthiazole-4-carboxamide, which exhibited oncolytic activity in patients with chronic myelogenous leukaemia (CML) in blast crisis was found to inhibit the growth of human neuroblastoma SK-N-SH cells with an IC50 of 4.2 μM. TR treatment of cells perturbed nucleic acid and catecholamine pathways. As biochemical markers of TR action decreased cellular GTP pools, increased inosine and hypoxanthine concentrations and depleted dopamine content were found. Incubation of tumour specimens obtained from paediatric patients with grade-IV neuroblastoma with TR resulted in the formation of the active metabolite, thiazole-4-carboxamide adenine dinucleotide, in concentrations sufficient to inhibit tumour growth. Cytotoxic and biochemical effects of TR were enhanced by combining it with allopurinol (an inhibitor of xanthine dehydrogenase), and hypoxanthine (an alternate substrate for hypoxanthine-guanine phosphoribosyltransferase). Induction of transdifferentiation of SK-N-SH cells from a neuroblast to an epitheloid, substrate-adherent phenotype was more pronounced with TR than with all-trans-retinoic acid. Transdifferentiating treatment with TR resulted in a 2-fold-enhanced sensitivity towards adriamycin. However, differentiation with all-trans-retinoic acid rendered the cells more resistant to adriamycin. Our results suggest that TR might be a promising agent for the treatment of children suffering from neuroblastoma.

Original languageEnglish (US)
Pages (from-to)92-95
Number of pages4
JournalInternational Journal of Cancer
Volume55
Issue number1
StatePublished - 1993
Externally publishedYes

Fingerprint

tiazofurin
Neuroblastoma
Hypoxanthine
Tretinoin
Doxorubicin
IMP Dehydrogenase
Xanthine Dehydrogenase
Blast Crisis
Hypoxanthine Phosphoribosyltransferase
Inosine
Allopurinol
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Growth
Guanosine Triphosphate
Nucleic Acids
Inhibitory Concentration 50
Catecholamines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pillwein, K., Schuchter, K., Ressmann, G., Gharenbaghi, K., Knoflach, A., Cermak, B., ... Chiba, P. (1993). Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells. International Journal of Cancer, 55(1), 92-95.

Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells. / Pillwein, K.; Schuchter, K.; Ressmann, G.; Gharenbaghi, K.; Knoflach, A.; Cermak, B.; Jayaram, H. N.; Szalay, S. M.; Szekeres, T.; Chiba, P.

In: International Journal of Cancer, Vol. 55, No. 1, 1993, p. 92-95.

Research output: Contribution to journalArticle

Pillwein, K, Schuchter, K, Ressmann, G, Gharenbaghi, K, Knoflach, A, Cermak, B, Jayaram, HN, Szalay, SM, Szekeres, T & Chiba, P 1993, 'Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells', International Journal of Cancer, vol. 55, no. 1, pp. 92-95.
Pillwein K, Schuchter K, Ressmann G, Gharenbaghi K, Knoflach A, Cermak B et al. Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells. International Journal of Cancer. 1993;55(1):92-95.
Pillwein, K. ; Schuchter, K. ; Ressmann, G. ; Gharenbaghi, K. ; Knoflach, A. ; Cermak, B. ; Jayaram, H. N. ; Szalay, S. M. ; Szekeres, T. ; Chiba, P. / Cytotoxicity, differentiating activity and metabolism of tiazofurin in human neuroblastoma cells. In: International Journal of Cancer. 1993 ; Vol. 55, No. 1. pp. 92-95.
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