Novel functions for an old drug: DFMO effects on cellular autophagy and T. cruzi infection

VANRELL MC; BARCLAY JJ; CARRILLO C; GOTTLIEB R; ROMANO PS

Sao Paulo

Simposio; II Symposium on Drug Design and Development for Neglected Diseases.; 2011

Introduction and Objective:Trypanosomatids depend on spermidine for growth and survival. Consequently, enzymes involved in spermidine synthesis and utilization, like ornithine decarboxylase (ODC), are promising targets for drug development. In this context, the ODC inhibitor alpha-difluoromethylornithine (DFMO) has been used as therapy in the African trypanosomiasis because it was demonstrated to be active against human late-stage gambiense sleeping sickness. In the case of American trypanosomiasis, it has been demonstrated that ODC, the DFMO target enzyme, is absent in Trypanosoma cruzi (Carrillo et al, 1999). Autophagy is the cell process that recycles cytoplasmic components and aged or damaged organelles. Previously we have shown that T. cruzi interacts with autophagosomes during host cell invasion (Romano et al, 2009). Based on the fact that spermidine is a positive regulator of autophagy in host cells (Einsenberg et al, 2009), the aim of this work was to analyze the effect of DFMO or polyamine depletion on T. cruzi infection and autophagic response of the host cell. Results and Conclusion:Our results show that reduction of PA cellular levels with DFMO produces a strong inhibition of autophagy under starvation and even under Rapamycin treatment. Furthermore pretreatment of host cells with DFMO significantly reduce T. cruzi infection of cells under starvation and control conditions. In contrast, pretreatment of parasites with DFMO have no effect over cell infection as it was shown previously. Considering that DFMO is an FDA approved drug and that autophagy inhibitors like wortmannin or 3-methyl adenine are unspecific and highly toxic drugs, we propose DFMO as a novel physiological compound that efficiently reduce the negative effects of autophagy activation under particular circumstances. Studies on animal models will be conducted to test the possible efficiency of this drug on in vivo T. cruzi infections as by self or in combined therapies.