Effect of hydroxyurea on the intracellular multiplication of Toxoplasma gondii, Leishmania amazonensis and Trypanosoma cruzi

Abstract

Toxoplasma gondii, Leishmania amazonensis and Trypanosoma cruzi are obligate intracellular parasites that multiply until lysis of host cells. The present study was undertaken to evaluate the effect of hydroxyurea (an inhibitor of cell division at the G1/S phase) on the multiplication of L. amazonensis, T. gondii, and T. cruzi in infected host cells. Infected cells were treated with hydroxyurea (4 mM) for 48 h. Hydroxyurea arrested intracellular multiplication of all infective forms of the parasites tested. In treated cultures, the percent of infected host cells decreased (50-97%) and most intracellular parasites were eliminated. Ultrastructural observations showed no morphologic change in host cells while intracellular parasites presented drastic morphologic alterations or disruption. The results strongly suggest that hydroxyurea was able to interfere with the multiplication of intracellular parasites, leading to an irreversible morphological effect on L. amazonensis, T. gondii, and T. cruzi without affecting the host cells.

Synthesis of thiosemicarbazone and 4-thiazolidinone derivatives and their in vitro anti-Toxoplasma gondii activity

“…1a). 7 HU acts by blocking the activity of the enzyme ribonucleotide reductase, arresting the cell cycle in the G1/S phase and, then, inactivating the DNA synthesis. 2 However, HU has a low affinity for the ribonucleotide reductase and a short half-life in humans.…”

Anti-parasitic action and elimination of intracellular Toxoplasma gondii in the presence of novel thiosemicarbazone and its 4-thiazolidinone derivatives

“…Infection was also reduced by incubation with HU to a level similar to that observed for the new compounds (Figure 2). HU used for comparison (11,12) was 4 mM and other compounds were 1 mM. The reduction in infection was closely associated with the disorganization and elimination of normal parasites after 12 h of treatment, at which point morphologically normal tachyzoites were greatly decreased in number ( Figure 2C).…”

“…We initially used an anti-proliferative drug hydroxyurea (HU) against intracellular parasites such as T. gondii, Leishmania amazonensis and Trypanosoma cruzi. This drug arrested the replication of these microorganisms, resulting in parasite elimination and reduced infection in vitro (11,12).…”

Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice

“…HU treatment of macrophages infected by Toxoplasma gondii , Leishmania amazonensis , Trypanosoma cruzi , and L. mexicana has been shown to drastically reduce the number of infected cells (Melo and Beiral, 2003; Martinez-Rojano et al, 2008). Therefore, we tested whether HU would compromise the intracellular growth of Cn cells.…”

“…This hypothesis is supported by our experiment with macrophage-like cell line showing that HU significantly suppresses fungal cell division within macrophages. Very interestingly, HU has been tested against various intracellular parasites such as Toxoplasma gondii , L. amazonensis , Trypanosoma cruzi , and L. mexicana (Melo and Beiral, 2003; Martinez-Rojano et al, 2008). Not only did HU induce morphological changes in these parasites, but also it inhibited intracellular multiplication of these microbes, similar to the phenotype observed with Cn in macrophages illustrated in this paper.…”