The Role of S-Adenosylmethionine Synthetase in Killing Effects of DFMO in African Trypanosomes
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T. brucei parasites cause a fatal disease that affects hundreds of thousands of people in sub-Saharan Africa. Since current treatment options show either poor efficacy or have safety concerns, it is necessary to identify new targets in the parasite for the development of better medication against this disease. The purpose of my work was to investigate the role of a functional AdoMetSyn in the toxic effect of eflornithine, a clinically used therapy for the treatment of the disease. Prior studies suggested that the toxicity of eflornithine may be due to the combined effect of polyamine depletion and detrimental effects of increased levels of AdoMet in the cell. In order to further study this effect I generated an RNAi cell line that allowed me to test the effects of decreasing S-Adenosylmethionine Synthetase (AdoMetSyn) levels on eflornithine toxicity. I found that knockdown of AdoMetSyn mRNA led to reduced growth rates and to a reduction in AdoMet and dcAdoMet levels in the cell. The potency of DFMO was increased when tested on the RNAi cells containing reduced AdoMet levels. Thus my studies do not provide support for the hypothesis that elevated levels of AdoMet lead to potentiation of the eflornithine anti-growth effects. These results can prove useful in improving DFMO treatment of trypanosomiasis in infected patients.