Effects of sodium stibogluconate on differentiation and proliferation of human myeloid leukemia cell lines in vitro

Abstract

PTPases are key signaling molecules and targets for developing novel therapeutics. We have studied the in vitro biological activity of PTPase inhibitor sodium stibogluconate (SS) on differentiation and proliferation of myeloid leukemia cell lines (NB4, HL-60 and U937). SS (250 g/ml, 6 days) induced 87% of NB4 cells to reduce nitroblue tetrazolium (NBT), in comparison to the 90% induced by ATRA (1 M, 6 days). SS treatment of NB4 cells resulted in an increase of CD11b expression and of a morphologically more mature population, coincident with growth arrest at S phase and increased cell death. The effect of SS on NB4 differentiation was irreversible and required continuous drug exposure. SS (400 g/ml, 6 days) induced 60% and 55% of NBT-positive cells in HL-60 and U937 cell lines, which were augmented in the presence of GM-CSF (25 ng/ml) to levels (85% and 81%, respectively) comparable to those induced by ATRA. SS induced increased tyrosine phosphorylation of cellular proteins in the AML cell lines and inactivated SHP-1 PTPase in NB4 cells, consistent with SS functioning as a PTPase inhibitor in the leukemia cells. These results provide the first evidence of an anti-leukemia activity of SS as a PTPase inhibitor.

HIV‐1 Replication Is Stimulated by Sodium Stibogluconate, the Therapeutic Mainstay in the Treatment of Leishmaniasis

“…First, the sodium stibogluconate-induced phosphatase inhibition could lead to a very weak increase in tyrosine phosphorylation of key signaling molecules and, hence, to a slow accumulation in the nucleus of the transcription factors necessary to drive HIV-1 LTR transcription. Indeed, Western-blot analysis of sodium stibogluconate-treated CD4 + T cells with the phosphotyrosine-specific antibody 4G10 revealed a very weak and transient increase in tyrosine-phosphorylated proteins (data not shown), which is in agreement with observations made in myeloid cell lines [14,27,28]. Second, sodium stibogluconate could act indirectly, through the secretion of a soluble factor that would, in turn, activate HIV-1 expression in an autocrine and/or paracrine fashion.…”

Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects

“…SSG, a drug effective for chronic leishmaniasis [11], was a multi-PTPs inhibitor and augmented anti-cancer activity of IFN-alpha2b in mouse models [11][12][13][14]. Since it is selectively toxic to intracellular bur not free-living forms of the parasite [27][28][29][30] and intracellular survival of the pathogen in macrophages involves attenuation of cytokine signaling through PTPs [31], inhibition of PTPases may also provide an explanation for its antiparasitic activity.…”

“…Targeting intracellular PTPs by SSG was suggested by the reduced PTP activity of SHP-1 and SHP-2 from cells cultured in the presence of SSG (10 mcg/ml) [13,14]. At clinically achievable level of the drug when administered at half the currently recommended dose (10 mg/kg body weight), SSG inhibited recombinant SHP-1 (100%), SHP-2 (80%) and PTP1B (70%) [12,15].…”

“…Our prior studies had identified sodium stibogluconate (SSG), a drug used for nearly 60 years to treat visceral leishmaniasis in humans [11], as a potent inhibitor of multi-PTPs that include SHP-1 and other PTPs critical in negative regulation cytokine signaling and immunity [12][13][14]. Targeting intracellular PTPs by SSG was suggested by the reduced PTP activity of SHP-1 and SHP-2 from cells cultured in the presence of SSG (10 mcg/ml) [13,14].…”

Anticancer Activity of Molecular Compounds of Arsenic, Antimony and Bismuth

“…Some of the antimony compounds used for the treatment of leishmaniasis have also been investigated for potential antitumour activity [56][57][58][59]. Sodium stibogluconate has been evaluated for antileukaemic activity against the myeloid leukaemia cell lines (NB4, HL-60 and U937) and shown to induce differentiation of acute myeloid leukaemia.…”