Effect of the alkyl-lysophospholipids on the proliferation and differentiation of Trypanosoma cruzi.
Alkyl-lysophospholipids (ALPs), designed as potential immunomodulators, have been shown to be cytotoxic for a variety of tumour cells and are under clinical studies for cancer chemotherapy. ET-18-OCH(3), hexadecylphosphocholine and ilmofosine were assayed against the three forms of Trypanosoma cruzi. Incubation with bloodstream trypomastigotes resulted, under different experimental conditions, in higher activity of the compounds in comparison with crystal violet. The ED(50)/24 h values were 13.4+/-2.8 microM and 11. 7+/-0.6 microM for amastigotes and epimastigotes, respectively. ET-18-OCH(3) (0.3 and 0.6 microM) inhibited the differentiation of epimastigotes to trypomastigotes (Dm28C clone) in the range 40-57%. This drug (3.75-15 microM) also caused a time- and dose-dependent inhibition of the intracellular proliferation of amastigotes in heart muscle cells with ED(50) values of 14.3+/-4.2, 8.9+/-1.9 and 6. 8+/-0.4 microM, after 1, 2 and 3 days of treatment. Pre-treatment of the parasite with this drug inhibited its interiorization into the host cell. Interestingly, the intracellular differentiation of amastigotes to trypomastigotes was not hampered by the drug. The present results demonstrate the lytic effect of ALPs on the three forms of T. cruzi, as well as the inhibition of both the differentiation to the infective form and the proliferation of parasites interiorized in heart cells. Ultrastructural analysis of epimastigotes treated with the three ALPs showed extensive blebing of the flagellar membrane. As described in tumour cells, the membrane seems to be a primary target of the drugs.
Santa-Rita
R M
RM
Laboratório de Biologia Celular, DUBC, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, CP 926, 21045-900, Rio de Janeiro, Brazil.
Santos Barbosa
H
H
Meirelles
M N
MN
de Castro
S L
SL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000469:parasitology; D008018:Life Cycle Stages / Q000187:drug effects*; D008246:Lysophospholipids / Q000494:pharmacology*; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008854:Microscopy, Electron; D010742:Phospholipid Ethers / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D013696:Temperature; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure
D000970:Antineoplastic Agents; D008246:Lysophospholipids; D010742:Phospholipid Ethers; D010767:Phosphorylcholine; C026659:edelfosine; C039128:miltefosine; C043297:ilmofosine