Cargando…
Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation
Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies at pediatric ages and is characterized by different chromosomal rearrangements and genetic abnormalities involved in the differentiation and proliferation of lymphoid precursor cells. Brusatol is a quassinoid pla...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496058/ https://www.ncbi.nlm.nih.gov/pubmed/36140308 http://dx.doi.org/10.3390/biomedicines10092207 |
_version_ | 1784794175259017216 |
---|---|
author | Jorge, Joana Magalhães, Nisa Alves, Raquel Lapa, Beatriz Gonçalves, Ana Cristina Sarmento-Ribeiro, Ana Bela |
author_facet | Jorge, Joana Magalhães, Nisa Alves, Raquel Lapa, Beatriz Gonçalves, Ana Cristina Sarmento-Ribeiro, Ana Bela |
author_sort | Jorge, Joana |
collection | PubMed |
description | Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies at pediatric ages and is characterized by different chromosomal rearrangements and genetic abnormalities involved in the differentiation and proliferation of lymphoid precursor cells. Brusatol is a quassinoid plant extract extensively studied due to its antineoplastic effect through global protein synthesis and nuclear factor erythroid 2-related factor-2 (NRF2) signaling inhibition. NRF2 is the main regulator of cellular antioxidant response and reactive oxygen species (ROS), which plays an important role in oxidative stress regulation. This study aimed to evaluate the effect of brusatol in in vitro models of ALL. KOPN-8 (B-ALL), CEM (T-ALL), and MOLT-4 (T-ALL) cell lines were incubated with increasing concentrations of brusatol, and the metabolic activity was evaluated using the resazurin assay. Flow cytometry was used to evaluate cell death, cell cycle, mitochondrial membrane potential (Δψ(mit)), and to measure ROS and reduced glutathione (GSH) levels. Our results show that brusatol promoted a decrease in metabolic activity in ALL cell lines in a time-, dose-, and cell-line-dependent manner. Brusatol induced a cytostatic effect by cell cycle arrest in G(0)/G(1) in all cell lines; however, cell death mediated by apoptosis was only observed in T-ALL cells. Brusatol leads to an oxidative stress imbalance by the increase in ROS levels, namely, superoxide anion. Redox imbalance and cellular apoptosis induced by brusatol are highly modulated by mitochondria disruption as a decrease in mitochondrial membrane potential is detected. These data suggest that brusatol might represent a new therapeutic approach for acute lymphoblastic leukemia, particularly for ALL T-cell lineage. |
format | Online Article Text |
id | pubmed-9496058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94960582022-09-23 Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation Jorge, Joana Magalhães, Nisa Alves, Raquel Lapa, Beatriz Gonçalves, Ana Cristina Sarmento-Ribeiro, Ana Bela Biomedicines Article Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies at pediatric ages and is characterized by different chromosomal rearrangements and genetic abnormalities involved in the differentiation and proliferation of lymphoid precursor cells. Brusatol is a quassinoid plant extract extensively studied due to its antineoplastic effect through global protein synthesis and nuclear factor erythroid 2-related factor-2 (NRF2) signaling inhibition. NRF2 is the main regulator of cellular antioxidant response and reactive oxygen species (ROS), which plays an important role in oxidative stress regulation. This study aimed to evaluate the effect of brusatol in in vitro models of ALL. KOPN-8 (B-ALL), CEM (T-ALL), and MOLT-4 (T-ALL) cell lines were incubated with increasing concentrations of brusatol, and the metabolic activity was evaluated using the resazurin assay. Flow cytometry was used to evaluate cell death, cell cycle, mitochondrial membrane potential (Δψ(mit)), and to measure ROS and reduced glutathione (GSH) levels. Our results show that brusatol promoted a decrease in metabolic activity in ALL cell lines in a time-, dose-, and cell-line-dependent manner. Brusatol induced a cytostatic effect by cell cycle arrest in G(0)/G(1) in all cell lines; however, cell death mediated by apoptosis was only observed in T-ALL cells. Brusatol leads to an oxidative stress imbalance by the increase in ROS levels, namely, superoxide anion. Redox imbalance and cellular apoptosis induced by brusatol are highly modulated by mitochondria disruption as a decrease in mitochondrial membrane potential is detected. These data suggest that brusatol might represent a new therapeutic approach for acute lymphoblastic leukemia, particularly for ALL T-cell lineage. MDPI 2022-09-06 /pmc/articles/PMC9496058/ /pubmed/36140308 http://dx.doi.org/10.3390/biomedicines10092207 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Jorge, Joana Magalhães, Nisa Alves, Raquel Lapa, Beatriz Gonçalves, Ana Cristina Sarmento-Ribeiro, Ana Bela Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation |
title | Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation |
title_full | Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation |
title_fullStr | Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation |
title_full_unstemmed | Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation |
title_short | Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation |
title_sort | antitumor effect of brusatol in acute lymphoblastic leukemia models is triggered by reactive oxygen species accumulation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9496058/ https://www.ncbi.nlm.nih.gov/pubmed/36140308 http://dx.doi.org/10.3390/biomedicines10092207 |
work_keys_str_mv | AT jorgejoana antitumoreffectofbrusatolinacutelymphoblasticleukemiamodelsistriggeredbyreactiveoxygenspeciesaccumulation AT magalhaesnisa antitumoreffectofbrusatolinacutelymphoblasticleukemiamodelsistriggeredbyreactiveoxygenspeciesaccumulation AT alvesraquel antitumoreffectofbrusatolinacutelymphoblasticleukemiamodelsistriggeredbyreactiveoxygenspeciesaccumulation AT lapabeatriz antitumoreffectofbrusatolinacutelymphoblasticleukemiamodelsistriggeredbyreactiveoxygenspeciesaccumulation AT goncalvesanacristina antitumoreffectofbrusatolinacutelymphoblasticleukemiamodelsistriggeredbyreactiveoxygenspeciesaccumulation AT sarmentoribeiroanabela antitumoreffectofbrusatolinacutelymphoblasticleukemiamodelsistriggeredbyreactiveoxygenspeciesaccumulation |