Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells

Thomas Szekeres, Monika Fritzer, Herbert Strobl, Kamran Gharehbaghi, Gabriele Findenig, Howard L. Elford, Christian Lhotka, Hans J. Schoen, Hiremagalur N. Jayaram

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Abstract

Increased ribonucleotide reductase (RR) activity has been linked with malignant transformation and tumor cell growth. Therefore, this enzyme is considered to be an excellent target for cancer chemotherapy. We have examined the effects of a newly patented RR inhibitor, trimidox (3,4,5- trihydroxybenzohydroxamidoxime). Trimidox inhibited the growth of human promyelocytic leukemia HL-60 cells with an IC50 of 35 μmol/L. Incubation of HL-60 cells with 50 μmol/L trimidox for 24 hours decreased deoxyguanosine triphosphate (dGTP) and deoxycytidine triphosphate (dCTP) pools to 24% and 39% of control values, respectively. Incubation of HL-60 cells with 20 to 80 μmol/L trimidox even up to a period of 4 days did not alter the distribution of cells in different phases of cell cycle. Sequential incubation of HL-60 cells with trimidox (25 μmol/L) for 24 hours and then with 10 μmol/L tiazofurin (an inhibitor of inosine monophosphate dehydrogenase) for 4 days produced synergistic growth inhibitory activity, and the cell number decreased to 16% of untreated controls. When differentiation-linked cell surface marker expressions were determined in cells treated with trimidox and tiazofurin, a significantly increased fluorescence intensity was observed for the CD 11b (2.9-fold), CD 33 (1.9-fold), and HLA-D cell surface antigens. Expression of the transferrin receptor (CD71) increased 7.3-fold in cells treated with both agents, compared with untreated controls. Our results suggest that trimidox in combination with tiazofurin might be useful in the treatment of leukemia.

Original languageEnglish
Pages (from-to)4316-4321
Number of pages6
JournalBlood
Volume84
Issue number12
StatePublished - Dec 15 1994

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tiazofurin
HL-60 Cells
Ribonucleotide Reductases
Leukemia
Growth
HLA-D Antigens
Inosine Monophosphate
Transferrin Receptors
Chemotherapy
Cell growth
Surface Antigens
Somatostatin-Secreting Cells
Tumors
Oxidoreductases
Fluorescence
Cells
Inhibitory Concentration 50
Cell Differentiation
Neoplasms
Cell Cycle

ASJC Scopus subject areas

  • Hematology

Cite this

Szekeres, T., Fritzer, M., Strobl, H., Gharehbaghi, K., Findenig, G., Elford, H. L., ... Jayaram, H. N. (1994). Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells. Blood, 84(12), 4316-4321.

Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells. / Szekeres, Thomas; Fritzer, Monika; Strobl, Herbert; Gharehbaghi, Kamran; Findenig, Gabriele; Elford, Howard L.; Lhotka, Christian; Schoen, Hans J.; Jayaram, Hiremagalur N.

In: Blood, Vol. 84, No. 12, 15.12.1994, p. 4316-4321.

Research output: Contribution to journalArticle

Szekeres, T, Fritzer, M, Strobl, H, Gharehbaghi, K, Findenig, G, Elford, HL, Lhotka, C, Schoen, HJ & Jayaram, HN 1994, 'Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells', Blood, vol. 84, no. 12, pp. 4316-4321.
Szekeres T, Fritzer M, Strobl H, Gharehbaghi K, Findenig G, Elford HL et al. Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells. Blood. 1994 Dec 15;84(12):4316-4321.
Szekeres, Thomas ; Fritzer, Monika ; Strobl, Herbert ; Gharehbaghi, Kamran ; Findenig, Gabriele ; Elford, Howard L. ; Lhotka, Christian ; Schoen, Hans J. ; Jayaram, Hiremagalur N. / Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells. In: Blood. 1994 ; Vol. 84, No. 12. pp. 4316-4321.
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abstract = "Increased ribonucleotide reductase (RR) activity has been linked with malignant transformation and tumor cell growth. Therefore, this enzyme is considered to be an excellent target for cancer chemotherapy. We have examined the effects of a newly patented RR inhibitor, trimidox (3,4,5- trihydroxybenzohydroxamidoxime). Trimidox inhibited the growth of human promyelocytic leukemia HL-60 cells with an IC50 of 35 μmol/L. Incubation of HL-60 cells with 50 μmol/L trimidox for 24 hours decreased deoxyguanosine triphosphate (dGTP) and deoxycytidine triphosphate (dCTP) pools to 24{\%} and 39{\%} of control values, respectively. Incubation of HL-60 cells with 20 to 80 μmol/L trimidox even up to a period of 4 days did not alter the distribution of cells in different phases of cell cycle. Sequential incubation of HL-60 cells with trimidox (25 μmol/L) for 24 hours and then with 10 μmol/L tiazofurin (an inhibitor of inosine monophosphate dehydrogenase) for 4 days produced synergistic growth inhibitory activity, and the cell number decreased to 16{\%} of untreated controls. When differentiation-linked cell surface marker expressions were determined in cells treated with trimidox and tiazofurin, a significantly increased fluorescence intensity was observed for the CD 11b (2.9-fold), CD 33 (1.9-fold), and HLA-D cell surface antigens. Expression of the transferrin receptor (CD71) increased 7.3-fold in cells treated with both agents, compared with untreated controls. Our results suggest that trimidox in combination with tiazofurin might be useful in the treatment of leukemia.",
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