Cargando…

Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells

Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-o...

Descripción completa

Detalles Bibliográficos
Autores principales: Kostić, Ana, Jovanović Stojanov, Sofija, Podolski-Renić, Ana, Nešović, Marija, Dragoj, Miodrag, Nikolić, Igor, Tasić, Goran, Schenone, Silvia, Pešić, Milica, Dinić, Jelena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301827/
https://www.ncbi.nlm.nih.gov/pubmed/34209342
http://dx.doi.org/10.3390/brainsci11070884
_version_ 1783726761224175616
author Kostić, Ana
Jovanović Stojanov, Sofija
Podolski-Renić, Ana
Nešović, Marija
Dragoj, Miodrag
Nikolić, Igor
Tasić, Goran
Schenone, Silvia
Pešić, Milica
Dinić, Jelena
author_facet Kostić, Ana
Jovanović Stojanov, Sofija
Podolski-Renić, Ana
Nešović, Marija
Dragoj, Miodrag
Nikolić, Igor
Tasić, Goran
Schenone, Silvia
Pešić, Milica
Dinić, Jelena
author_sort Kostić, Ana
collection PubMed
description Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives—Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306—were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. Results: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. Conclusion: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations.
format Online
Article
Text
id pubmed-8301827
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83018272021-07-24 Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells Kostić, Ana Jovanović Stojanov, Sofija Podolski-Renić, Ana Nešović, Marija Dragoj, Miodrag Nikolić, Igor Tasić, Goran Schenone, Silvia Pešić, Milica Dinić, Jelena Brain Sci Article Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives—Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306—were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. Results: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. Conclusion: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations. MDPI 2021-06-30 /pmc/articles/PMC8301827/ /pubmed/34209342 http://dx.doi.org/10.3390/brainsci11070884 Text en © 2021 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
Kostić, Ana
Jovanović Stojanov, Sofija
Podolski-Renić, Ana
Nešović, Marija
Dragoj, Miodrag
Nikolić, Igor
Tasić, Goran
Schenone, Silvia
Pešić, Milica
Dinić, Jelena
Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
title Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
title_full Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
title_fullStr Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
title_full_unstemmed Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
title_short Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
title_sort pyrazolo[3,4-d]pyrimidine tyrosine kinase inhibitors induce oxidative stress in patient-derived glioblastoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301827/
https://www.ncbi.nlm.nih.gov/pubmed/34209342
http://dx.doi.org/10.3390/brainsci11070884
work_keys_str_mv AT kosticana pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT jovanovicstojanovsofija pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT podolskirenicana pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT nesovicmarija pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT dragojmiodrag pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT nikolicigor pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT tasicgoran pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT schenonesilvia pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT pesicmilica pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells
AT dinicjelena pyrazolo34dpyrimidinetyrosinekinaseinhibitorsinduceoxidativestressinpatientderivedglioblastomacells