Antiproliferative effect of dihydroxyacetone on Trypanosoma brucei bloodstream forms: cell cycle progression, subcellular alterations, and cell death.
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 G(2)/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.
Uzcátegui
Néstor L
NL
Interfaculty Institute of Biochemistry, University of Tuebingen, Germany. uzcategn@ucv.ve
Carmona-Gutiérrez
Didac
D
Denninger
Viola
V
Schoenfeld
Caroline
C
Lang
Florian
F
Figarella
Katherine
K
Duszenko
Michael
M
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004098:Dihydroxyacetone / Q000494:pharmacology*; D005434:Flow Cytometry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D017382:Reactive Oxygen Species; D014344:Trypanocidal Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); C023132:glycerone kinase; D004098:Dihydroxyacetone