Inhibition of c-myc expression in human promyelocytic leukemia and colon adenocarcinoma cells by 6-thioguanine

Edward L. Schwartz, Helena Chamberlin, Anna Barbara Brechbühl

Research output: Contribution to journalArticle

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Abstract

A rapid decrease in expression of the oncogene c-myc has been associated with the induction of differentiation of HL-60 human leukemia cells. In this manner, the treatment of a hypoxanthine phosphoribosyltransferase (HPRT)-deficient HL-60 variant (HL-60/var) with 6-thioguanine (TG) was accompanied by lower c-myc mRNA levels. This occurred in the absence of 6-thioguanosine 5'-monophosphate (TGMP) synthesis and without alterations in cellular nucleotide pool sizes. Paradoxically, inhibition of c-myc expression in the wild type HL-60 (HL-60/wt) cell, which is only weakly induced to differentiate by TG, was 5-fold more sensitive to the thiopurine (ic50 = 35 μM). Furthermore, inosine, which blocks the formation of TGMP and enhances the extent of differentiation of HL-60/wt cells, decreased the sensitivity of c-myc expression in the HL-60/wt to TG. These actions of TG and inosine on c-myc were also observed in the human colon carcinoma cell line COLO 320, further dissociating some of the effects of TG on c-myc expression from granylocytic differentiation. The hematopoietic granulocyte-macrophage colony stimulating factor (GM-CSF) elevated c-myc expression and antagonized the actions of TG on c-myc in the HL-60 cells. GM-CSF more readily antagonized the inhibitory action of TG in the HL-60/var cell line when compared to the HL-60/wt cells, restoring c-myc levels to that of the untreated controls. Hence, TG inhibited c-myc expression by two distinct mechanisms in cells which express high levels of the oncogene: a TGMP-dependent, differentiation-independent process with an ic50 of 35 μM, and a TGMP-independent action with an ic50 of 175 μM that was associated with induction of differentiation and was reversed more readily by GM-CSF.

Original languageEnglish (US)
Pages (from-to)2449-2455
Number of pages7
JournalBiochemical Pharmacology
Volume40
Issue number11
DOIs
StatePublished - Dec 1 1990

Fingerprint

Thioguanine
Colon
Leukemia
Adenocarcinoma
HL-60 Cells
Granulocyte-Macrophage Colony-Stimulating Factor
Inhibitory Concentration 50
Inosine
Cells
Hypoxanthine Phosphoribosyltransferase
Cell Line
myc Genes
Oncogenes
Nucleotides
Carcinoma
Messenger RNA

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of c-myc expression in human promyelocytic leukemia and colon adenocarcinoma cells by 6-thioguanine. / Schwartz, Edward L.; Chamberlin, Helena; Brechbühl, Anna Barbara.

In: Biochemical Pharmacology, Vol. 40, No. 11, 01.12.1990, p. 2449-2455.

Research output: Contribution to journalArticle

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abstract = "A rapid decrease in expression of the oncogene c-myc has been associated with the induction of differentiation of HL-60 human leukemia cells. In this manner, the treatment of a hypoxanthine phosphoribosyltransferase (HPRT)-deficient HL-60 variant (HL-60/var) with 6-thioguanine (TG) was accompanied by lower c-myc mRNA levels. This occurred in the absence of 6-thioguanosine 5'-monophosphate (TGMP) synthesis and without alterations in cellular nucleotide pool sizes. Paradoxically, inhibition of c-myc expression in the wild type HL-60 (HL-60/wt) cell, which is only weakly induced to differentiate by TG, was 5-fold more sensitive to the thiopurine (ic50 = 35 μM). Furthermore, inosine, which blocks the formation of TGMP and enhances the extent of differentiation of HL-60/wt cells, decreased the sensitivity of c-myc expression in the HL-60/wt to TG. These actions of TG and inosine on c-myc were also observed in the human colon carcinoma cell line COLO 320, further dissociating some of the effects of TG on c-myc expression from granylocytic differentiation. The hematopoietic granulocyte-macrophage colony stimulating factor (GM-CSF) elevated c-myc expression and antagonized the actions of TG on c-myc in the HL-60 cells. GM-CSF more readily antagonized the inhibitory action of TG in the HL-60/var cell line when compared to the HL-60/wt cells, restoring c-myc levels to that of the untreated controls. Hence, TG inhibited c-myc expression by two distinct mechanisms in cells which express high levels of the oncogene: a TGMP-dependent, differentiation-independent process with an ic50 of 35 μM, and a TGMP-independent action with an ic50 of 175 μM that was associated with induction of differentiation and was reversed more readily by GM-CSF.",
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