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Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells

About 95% of Glioblastoma (GBM) patients experience tumor relapse as a consequence of resistance to the first-line standard chemotherapy using temozolomide (TMZ). Recent studies reported consistently elevated expression levels of carbonic anhydrase CA2 in recurrent glioblastoma and temozolomide-resi...

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Autores principales: Zhao, Kai, Schäfer, Agnes, Zhang, Zhuo, Elsässer, Katharina, Culmsee, Carsten, Zhong, Li, Pagenstecher, Axel, Nimsky, Christopher, Bartsch, Jörg W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745118/
https://www.ncbi.nlm.nih.gov/pubmed/35008590
http://dx.doi.org/10.3390/ijms23010157
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author Zhao, Kai
Schäfer, Agnes
Zhang, Zhuo
Elsässer, Katharina
Culmsee, Carsten
Zhong, Li
Pagenstecher, Axel
Nimsky, Christopher
Bartsch, Jörg W.
author_facet Zhao, Kai
Schäfer, Agnes
Zhang, Zhuo
Elsässer, Katharina
Culmsee, Carsten
Zhong, Li
Pagenstecher, Axel
Nimsky, Christopher
Bartsch, Jörg W.
author_sort Zhao, Kai
collection PubMed
description About 95% of Glioblastoma (GBM) patients experience tumor relapse as a consequence of resistance to the first-line standard chemotherapy using temozolomide (TMZ). Recent studies reported consistently elevated expression levels of carbonic anhydrase CA2 in recurrent glioblastoma and temozolomide-resistant glioblastoma stem-like cells (GSCs). Here we show that CA2 is preferentially expressed in GSCs and upregulated by TMZ treatment. When expressed in GBM cell lines, CA2 exerts significant metabolic changes reflected by enhanced oxygen consumption and increased extracellular acidification causing higher rates of cell invasion. Notably, GBM cells expressing CA2 respond to combined treatment with TMZ and brinzolamide (BRZ), a non-toxic and potent CA2 inhibitor. Interestingly, brinzolamide was more effective than the pan-CA inhibitor Acetazolamide (ACZ) to sensitize naïve GSCs and TMZ-resistant GSCs to TMZ induced cell death. Mechanistically, we demonstrated that the combined treatment of GBM stem cells with TMZ and BRZ caused autophagy of GBM cell lines and GSCs, reflected by enhanced LC3 cleavage (LC3-II) and p62 reduction. Our findings illustrate the potential of CA2 as a chemo-sensitizing drug target in recurrent GBM and propose a combined treatment of TMZ with CA2 inhibitor to tackle GBM chemoresistance and recurrence.
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spelling pubmed-87451182022-01-11 Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells Zhao, Kai Schäfer, Agnes Zhang, Zhuo Elsässer, Katharina Culmsee, Carsten Zhong, Li Pagenstecher, Axel Nimsky, Christopher Bartsch, Jörg W. Int J Mol Sci Article About 95% of Glioblastoma (GBM) patients experience tumor relapse as a consequence of resistance to the first-line standard chemotherapy using temozolomide (TMZ). Recent studies reported consistently elevated expression levels of carbonic anhydrase CA2 in recurrent glioblastoma and temozolomide-resistant glioblastoma stem-like cells (GSCs). Here we show that CA2 is preferentially expressed in GSCs and upregulated by TMZ treatment. When expressed in GBM cell lines, CA2 exerts significant metabolic changes reflected by enhanced oxygen consumption and increased extracellular acidification causing higher rates of cell invasion. Notably, GBM cells expressing CA2 respond to combined treatment with TMZ and brinzolamide (BRZ), a non-toxic and potent CA2 inhibitor. Interestingly, brinzolamide was more effective than the pan-CA inhibitor Acetazolamide (ACZ) to sensitize naïve GSCs and TMZ-resistant GSCs to TMZ induced cell death. Mechanistically, we demonstrated that the combined treatment of GBM stem cells with TMZ and BRZ caused autophagy of GBM cell lines and GSCs, reflected by enhanced LC3 cleavage (LC3-II) and p62 reduction. Our findings illustrate the potential of CA2 as a chemo-sensitizing drug target in recurrent GBM and propose a combined treatment of TMZ with CA2 inhibitor to tackle GBM chemoresistance and recurrence. MDPI 2021-12-23 /pmc/articles/PMC8745118/ /pubmed/35008590 http://dx.doi.org/10.3390/ijms23010157 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
Zhao, Kai
Schäfer, Agnes
Zhang, Zhuo
Elsässer, Katharina
Culmsee, Carsten
Zhong, Li
Pagenstecher, Axel
Nimsky, Christopher
Bartsch, Jörg W.
Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells
title Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells
title_full Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells
title_fullStr Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells
title_full_unstemmed Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells
title_short Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells
title_sort inhibition of carbonic anhydrase 2 overcomes temozolomide resistance in glioblastoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745118/
https://www.ncbi.nlm.nih.gov/pubmed/35008590
http://dx.doi.org/10.3390/ijms23010157
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