A Betulinic Acid Derivative, BA5, Induces G0/G1 Cell Arrest, Apoptosis Like-Death, and Morphological Alterations in

Overview

Journal Front Pharmacol

Date 2022 Apr 8

PMID 35392556

Authors

Tatiana Barbosa Dos Santos Magalhaes

Dahara Keyse Carvalho Silva

Jessica da Silva Teixeira

Juliana Dizaira Teles De Lima

Jose Maria Barbosa-Filho

Diogo Rodrigo Magalhaes Moreira

Elisalva Teixeira Guimaraes

Milena Botelho Pereira Soares

Affiliations

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Abstract

Leishmaniasis are endemic diseases caused by different species of intracellular parasites of the genus . Due to the high toxicity and drug resistance of current antileishmanial drugs, it is necessary to identify new and more effective drugs. Previously, we investigated the immunomodulatory and anti- action of BA5, a derivative of betulinic acid. In the present study, we investigated the activity of BA5 against different species of and their action mechanism. BA5 exhibited low cytotoxicity against macrophages and inhibited the proliferation of promastigote forms of (IC = 4.5 ± 1.1 μM), (IC = 3.0 ± 0.8 μM), (IC = 0.9 ± 1.1 μM) and (IC = 0.15 ± 0.05 μM). Incubation with BA5 reduced the percentage of -infected macrophages and the number of intracellular parasites (IC = 4.1 ± 0.7 μM). To understand the mechanism of action underlying BA5 antileishmanial activity (incubation at IC/2 IC or 2xIC values of the drug), we investigated ultrastructural changes by scanning electron microscopy and evaluated cell cycle, membrane mitochondrial potential, and cell death against promastigote forms of by flow cytometry. Promastigotes incubated with BA5 presented membrane blebbing, flagella damage, increased size, and body deformation. Flow cytometry analysis showed that parasite death is mainly caused by apoptosis-like death, arrested cell cycle in G0/G1 phase and did not alter the membrane mitochondrial potential of . Surprisingly, the combination of BA5 and amphotericin B, an assay used to determine the degree of drug interaction, revealed synergistic effects (CI = 0.15 ± 0.09) on promastigotes forms of . In conclusion, BA5 compound is an effective and selective antileishmanial agent.

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