Uptake of the trypanocidal drug suramin by bloodstream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo

Fairlamb, Alan H.; Bowman, I.B.R.

doi:10.1016/0166-6851(80)90050-x

Cited by 97 publications

(54 citation statements)

References 30 publications

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“…Treatment with these drugs did not result in significant ES derepression. Treatment with the metabolic inhibitor suramin (46) or the ornithine decarboxylase inhibitor DFMO (35, 47) also had no detectable effect, despite inhibiting T. brucei cell growth in a comparable fashion to the other treatments (see "Experimental Procedures" for details). It is therefore likely that modification or damage of nuclear DNA is the key factor in the up-regulation of silent ESs that we observed.…”

Section: Dna Damage Results In the Up-regulation Of Gfp Markedmentioning

confidence: 99%

Bloodstream Form-specific Up-regulation of Silent VSG Expression Sites and Procyclin in Trypanosoma brucei after Inhibition of DNA Synthesis or DNA Damage

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Vruchte

Rudenko

2004

Journal of Biological Chemistry

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The African trypanosome Trypanosoma brucei transcribes the active variant surface glycoprotein (VSG) gene from one of about 20 VSG expression sites (ESs). In order to study ES control, we made reporter lines with a green fluorescent protein gene inserted behind the promoter of different ESs. We attempted to disrupt the silencing machinery, and we used fluorescence-activated cell sorter analysis for the rapid and sensitive detection of ES up-regulation. We find that a range of treatments that either block nuclear DNA synthesis, like aphidicolin, or modify DNA-like cisplatin and 1-methyl-3-nitro-1-nitrosoguanidine results in up-regulation of silent ESs. Aphidicolin treatment was the most effective, with almost 80% of the cells expressing green fluorescent protein from a silent ES. All of these treatments blocked the cells in S phase. In contrast, a range of toxic chemicals had little or no effect on expression. These included berenil and pentamidine, which selectively cleave the mitochondrial kinetoplast DNA, the metabolic inhibitors suramin and difluoromethylornithine, and the mitotic inhibitor rhizoxin. Up-regulation also affected other RNA polymerase I (pol I) transcription units, as procyclin genes were also up-regulated after cells were treated with either aphidicolin or DNA-modifying agents. Strikingly, this up-regulation of silent pol I transcription units was bloodstream form-specific and was not observed in insect form T. brucei. We postulate that the redistribution of a limiting bloodstream form-specific factor involved in both silencing and DNA repair results in the derepression of normally silenced pol I transcription units after DNA damage.

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Section: Dna Damage Results In the Up-regulation Of Gfp Markedmentioning

confidence: 99%

Bloodstream Form-specific Up-regulation of Silent VSG Expression Sites and Procyclin in Trypanosoma brucei after Inhibition of DNA Synthesis or DNA Damage

Sheader

Vruchte

Rudenko

2004

Journal of Biological Chemistry

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“…None of these enzymes binds ATP/ ADP, which is unexpected as the chemotherapeutic effects of suramin are often attributed to its ability to inhibit the binding of ATP and other nucleotides (47). There is evidence to show that the trypanocidal action of suramin results from the inhibition of ATP production by glycolysis (48), an enzymatic pathway that has evolved to bind phosphometabolites. Although the binding mode has previously remained elusive, it is not surprising that suramin and the chemically related AB80 and BDS molecules are found to occupy ADP/ATP binding sites, which are present in many glycolytic enzymes, and may explain the promiscuous behavior of this compound class.…”

Section: Mode Of Action Of Suramin-like Phenylmentioning

confidence: 99%

The Trypanocidal Drug Suramin and Other Trypan Blue Mimetics Are Inhibitors of Pyruvate Kinases and Bind to the Adenosine Site

Morgan

McNae

Nowicki

et al. 2011

Journal of Biological Chemistry

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Therapies against trypanosomatid-borne diseases have evolved from the historic work of Paul Ehrlich (1), who was the first to provide a rationale for a chemotherapeutic approach in the treatment of infectious diseases. He used a series of naphthalene dyes related to trypan red and trypan blue (see Fig. 1a) and demonstrated that they had trypanocidal activity. Trypan blue successfully cleared trypanosomatid infections in mouse models but were not successful in other mammals. Ehrlich noted in his mouse trials where he tested over 50 related diazo dyes that mice treated with trypan red retained a red color for weeks and even months. This side effect was a significant drawback to its use in human therapy, and the search for a colorless analog was pursued by chemists at Bayer, who synthesized Bayer 205, now known as suramin (see Fig. 1c), which is still used in the treatment of human African trypanosomiasis (sleeping sickness) caused by the parasitic protist Trypanosoma brucei (2). Additional uses for suramin have been explored in the treatment of human cancers (3) and HIV infection (4), where it was the first drug to show antiviral activity (5). It is evident from the mass of literature that suramin is a promiscuous inhibitor of many enzymes and receptors and shows a range of interesting clinically relevant effects (6, 7). Despite following none of the currently accepted criteria for drug-likeness (8), suramin and a number of diverse analogues (9, 10) are still of clinical interest in an ever growing repertoire of diseases (11-13).Suramin has been characterized as an inhibitor of T. brucei and mammalian glycolytic enzymes (14 -16) and has been shown to inhibit all seven of the T. brucei glycolytic enzymes isolated from glycosomes (peroxisome-like organelles specific for kinetoplastid protists that harbor the first seven glycolytic enzymes converting glucose into 3-phosphoglycerate) with IC 50 values between 3 and 100 M (15). The three glycolytic enzymes found in the cytosol (phosphoglycerate mutase, enolase, and pyruvate kinase (PYK) 2 (17)) were not examined in these experiments. The importance of glycolytic enzymes for the viability of T. brucei has been confirmed by RNAi knockdown of glycosomal and cytosolic enzymes (including PYK) with consequent death of the parasite (18,19

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“…During treatment regimens, suramin reaches concentrations of approximately 100 laM within the host bloodstream [45] and, although not actively concentrated in the parasite, it reaches intracellular concentrations of approximately 100 laM [6]. Since suramin has a Ki of 6.7 laM for OPTb, the inhibition of OP-Tb by suramin may be physiologically relevant and this may explain, at least in part, the trypanocidal action of suramin, which remains unelucidated [6].…”

Section: Resultsmentioning

confidence: 99%

A trypanosome oligopeptidase as a target for the trypanocidal agents pentamidine, diminazene and suramin

et al. 1998

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Uptake of the trypanocidal drug suramin by bloodstream forms of Trypanosoma brucei and its effect on respiration and growth rate in vivo

Cited by 97 publications

References 30 publications

Bloodstream Form-specific Up-regulation of Silent VSG Expression Sites and Procyclin in Trypanosoma brucei after Inhibition of DNA Synthesis or DNA Damage

Bloodstream Form-specific Up-regulation of Silent VSG Expression Sites and Procyclin in Trypanosoma brucei after Inhibition of DNA Synthesis or DNA Damage

The Trypanocidal Drug Suramin and Other Trypan Blue Mimetics Are Inhibitors of Pyruvate Kinases and Bind to the Adenosine Site

A trypanosome oligopeptidase as a target for the trypanocidal agents pentamidine, diminazene and suramin

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