Regulatory volume decrease in Leishmania mexicana: effect of anti-microtubule drugs

Francehuli Dagger,Carlos Ayesta,Elizabeth Valdivieso,Ana K Marcano

doi:10.1590/s0074-02762013000100014

Francehuli Dagger, Carlos Ayesta + Show 2 more

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https://doi.org/10.1590/s0074-02762013000100014

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Abstract

The trypanosomatid cytoskeleton is responsible for the parasite's shape and it is modulated throughout the different stages of the parasite's life cycle. When parasites are exposed to media with reduced osmolarity, they initially swell, but subsequently undergo compensatory shrinking referred to as regulatory volume decrease (RVD). We studied the effects of anti-microtubule (Mt) drugs on the proliferation of Leishmania mexicana promastigotes and their capacity to undergo RVD. All of the drugs tested exerted antiproliferative effects of varying magnitudes [ansamitocin P3 (AP3)> trifluoperazine > taxol > rhizoxin > chlorpromazine]. No direct relationship was found between antiproliferative drug treatment and RVD. Similarly, Mt stability was not affected by drug treatment. Ansamitocin P3, which is effective at nanomolar concentrations, blocked amastigote-promastigote differentiation and was the only drug that impeded RVD, as measured by light dispersion. AP3 induced 2 kinetoplasts (Kt) 1 nucleus cells that had numerous flagella-associated Kts throughout the cell. These results suggest that the dramatic morphological changes induced by AP3 alter the spatial organisation and directionality of the Mts that are necessary for the parasite's hypotonic stress-induced shape change, as well as its recovery.

Highlights

The trypanosomatid cytoskeleton is responsible for the parasite’s shape and it is modulated throughout the different stages of the parasite’s life cycle
We selected drugs that were previously reported to affect the proliferation of various Leishmania species, suggesting that these drugs may act on the nuclear Mts, the kts, the basal body or the assembly of new Mts, which is necessary for cytokinesis
The cell populations remained slender or ovalshaped with one motile flagellum at the anterior end of the cell body. This finding indicates that the antiproliferative effects of these drugs involved the inhibition of basal body replication, one of the earliest events of the cell cycle in Leishmania and trypanosomatids (Robinson & Gull 1991, Harmanton et al 2003)

Summary

Introduction

The trypanosomatid cytoskeleton is responsible for the parasite’s shape and it is modulated throughout the different stages of the parasite’s life cycle. When exposed to media of reduced osmolarity, Mts and Leishmania RVD Francehuli Dagger et al 85 promotes Mts assembly and blocks cytokinesis in various cell types, including trypanosomatids (Baum et al 1981, Hernandez 1996, Moulay et al 1996); two potent and widely used tricyclic compounds, the phenothiazine drugs trifluoperazine (TFP) and chlorpromazine, which has been reported to destabilize Mts and to exert leishmanicidal effect, respectively (Pearson et al 1982, 1984, Seebeck & Gehr 1983) and two members of the ansamitocin family of antibiotics, rhizoxin and ansamitocin P3, which are potent antiproliferative agents at micromolar and nanomolar concentrations and exert highly effective antitumor activity in vivo (Tanida et al 1979, Ootsu et al 1980, Takahashi et al 1989, 1990).

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