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Flavonoids from the Amazon plant Brosimum acutifolium induce C6 glioma cell line apoptosis by disrupting mitochondrial membrane potential and reducing AKT phosphorylation

Flavonoids from the Amazon plant Brosimum acutifolium induce C6 glioma cell line apoptosis by disrupting mitochondrial membrane potential and reducing AKT phosphorylation

Authors :
N.M.G. Couto
Chubert Bernardo Castro de Sena
Alejandro F. Prado
Barbarella de Matos Macchi
Luis Antônio Loureiro Maués
Maria Elena Crespo-Lopez
Edilene O. Silva
G.M. Alves
B.J.M. da Silva
Mara S.P. Arruda
J.L.M. do Nascimento
Source :
Biomedicine & Pharmacotherapy, Vol 113, Iss, Pp-(2019)
Publication Year :
2019
Publisher :
Elsevier, 2019.

Abstract

Glioblastoma, which is highly invasive and has a poor patient prognosis, is the most common type of brain tumor. Flavonoids have known antiproliferative and antineoplastic effects, such as apoptosis induction and tumor growth inhibition. We investigated the effects of treatment with three flavonoids (BAS-1, BAS-4, and BAS-6) isolated from the Amazon plant Brosimum acutifolium on the proliferation and migration of the C6 glioma cell line. Cytotoxicity was evaluated by MTT assay, and morphological changes were evaluated by phase-contrast microscopy and by transmission electron microscopy. Apoptosis was determined using Annexin V-FITC-propidium iodide (PI) staining. A hemolysis assay was used to evaluate plasma membrane injury. Antiproliferative effects were assessed by wound migration and colony formation assays. Mitochondrial transmembrane potential (ΔΨm) was determined using JC-1 dye and flow cytometry. To identify the flavonoid targets, western blotting was performed. BAS-1 and BAS-4 reduced C6 cell proliferation in a dose-dependent manner. BAS-6 showed no effect. Due to its high toxicity toward primary glial cells and its high hemolytic index, BAS-1 was not used in the remaining experiments. BAS-4 treatment did not induce cytotoxicity in primary glial cells; however, in glioma cells, it suppressed migration and invasion and led to apoptosis through mitochondrial damage, ΔΨm loss, cell cycle arrest, and reduced AKT phosphorylation, which is a component of the main cell survival pathway. We conclude that BAS-4 showed potential activity against glioma by inducing apoptosis mediated by ΔΨm loss and AKT pathway disruption, and future studies should further evaluate BAS-4 as a promising antineoplastic agent against glioblastoma.

Details

Language :
English
ISSN :
07533322
Volume :
113
Database :
OpenAIRE
Journal :
Biomedicine & Pharmacotherapy
Accession number :
edsair.doi.dedup.....46034b1d823af87530f52d2b0cc63afe