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Antiproliferative Effect of Dihydroxyacetone on Trypanosoma brucei Bloodstream Forms: Cell Cycle Progression, Subcellular Alterations, and Cell Death

Néstor L. Uzcátegui,^1* Didac Carmona-Gutiérrez,^1, Viola Denninger,¹ Caroline Schoenfeld,¹ Florian Lang,² Katherine Figarella,^1, and Michael Duszenko^1*

Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany,¹ Institute of Physiology, University of Tuebingen, Tuebingen, Germany²

Received 28 March 2007/ Returned for modification 24 May 2007/ Accepted 27 July 2007

We evaluated the effects of dihydroxyacetone (DHA) on Trypanosoma brucei bloodstream forms. DHA is considered an energy source for many different cell types. T. brucei takes up DHA readily due to the presence of aquaglyceroporins. However, the parasite is unable to use it as a carbon source because of the absence of DHA kinase (DHAK). We could not find a homolog of the relevant gene in the genomic database of T. brucei and have been unable to detect DHAK activity in cell lysates of the parasite, and the parasite died quickly if DHA was the sole energy source in the medium. In addition, during trypanosome cultivation, DHA induced growth inhibition with a 50% inhibitory concentration of about 1 mM, a concentration that is completely innocuous to mammals. DHA caused cell cycle arrest in the G₂/M phase of up to 70% at a concentration of 2 mM. Also, DHA-treated parasites showed profound ultrastructural alterations, including an increase of vesicular structures within the cytosol and the presence of multivesicular bodies, myelin-like structures, and autophagy-like vacuoles, as well as a marked disorder of the characteristic mitochondrion structure. Based on the toxicity of DHA for trypanosomes compared with mammals, we consider DHA a starting point for a rational design of new trypanocidal drugs.

Published ahead of print on 6 August 2007.

Present address: Institute for Molecular Biosciences, University of Graz, Graz, Austria.

Present address: Fundación Instituto de Estudios Avanzados IDEA, Caracas, Venezuela.