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Abstract
The proteasome inhibitor and anti-cancer drug bortezomib was tested for in vitro activity against bloodstream forms of Trypanosoma brucei. The concentrations of bortezomib required to reduce the growth rate by 50% and to kill all trypanosomes were 3.3 nM and 10 nM, respectively. In addition, bortezomib was 10 times more toxic to trypanosomes than to human HL-60 cells. Moreover, exposure of trypanosomes to 10 nM bortezomib for 16 h was enough to kill 90% of the parasites following incubation in fresh medium. However, proteasomal peptidase activities of trypanosomes exposed to bortezomib were only inhibited by 10% and 30% indicating that the proteasome is not the main target of the drug. The results suggest that bortezomib may be useful as drug for the treatment of human African trypanosomiasis.
Highlights
Human African trypanosomiasis or sleeping sickness is a fatal disease caused by the protozoan parasite Trypanosoma brucei
There are only four drugs available for chemotherapy of sleeping sickness and all show some degree of toxic side effects [2]
At the turn of the millennium, the production of anti-sleeping sickness drugs was under threat as their manufacture was not profitable [5]
Summary
Human African trypanosomiasis or sleeping sickness is a fatal disease caused by the protozoan parasite Trypanosoma brucei. The GI50 and MIC ratios of cytotoxic/trypanocidal activities (selectivity indices) for bortezomib were less favourable (GI50 ratio = 8; MIC ratio = 10) than that of the anti-sleeping sickness drug melarsoprol (GI50 ratio = 860; MIC ratio = 100). As 10 nM is the MIC value of bortezomib, we wanted to investigate whether exposure of trypanosomes to 10 nM of the drug for 16 h is long enough to kill the parasites To this end, 5 × 105 trypanosomes/ml were treated with or without 10 nM bortezomib for 16 h, diluted to 104 cells/ml in fresh medium for further incubation and counted every 24 h using a Neubauer haemocytometer. Such drug combination regimes may lead to synergistic effects, in which lower amounts of drugs sufficient to kill the parasites would lead to a reduction in toxicity
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