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

Area of Science:

• Parasitology
• Cell Biology
• Pharmacology

Background:

• The trypanosomatid cytoskeleton, crucial for parasite shape, dynamically changes during life cycle stages.
• Parasites exhibit regulatory volume decrease (RVD) to counteract hypotonic swelling.
• Microtubules (Mt) are key components of the cytoskeleton in parasites like Leishmania.

Purpose of the Study:

• To investigate the impact of anti-microtubule (Mt) drugs on Leishmania mexicana promastigote proliferation.
• To assess the effect of these drugs on the parasite's ability to perform regulatory volume decrease (RVD).
• To understand the relationship between Mt drug treatment, proliferation, RVD, and Mt stability.

Main Methods:

• Treatment of Leishmania mexicana promastigotes with various anti-microtubule drugs.
• Assessment of antiproliferative effects and dose-dependent responses.
• Measurement of regulatory volume decrease (RVD) using light dispersion.
• Evaluation of microtubule (Mt) stability post-drug treatment.

Main Results:

• All tested drugs showed antiproliferative effects, with Ansamitocin P3 (AP3) being the most potent.
• No direct correlation was observed between antiproliferative activity and RVD capacity.
• Microtubule stability remained unaffected by the drug treatments.
• AP3 inhibited amastigote-promastigote differentiation and significantly impeded RVD.
• AP3 induced abnormal cell morphology, including multiple kinetoplasts and nuclei, with altered Mt organization.

Conclusions:

• Ansamitocin P3 disrupts Leishmania mexicana RVD and differentiation, likely by altering microtubule spatial organization.
• The parasite's ability to undergo hypotonic stress-induced shape changes is dependent on proper microtubule organization.
• Microtubule-targeting drugs can have complex effects on parasite physiology beyond simple proliferation inhibition.