Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells

Zhao, Kai; Schäfer, Agnes; Zhang, Zhuo; Elsässer, Katharina; Culmsee, Carsten; Zhong, Julia Li; Pagenstecher, Axel; Nimsky, Christopher; Bartsch, Jörg W.

doi:10.3390/ijms23010157

Cited by 16 publications

(13 citation statements)

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“…A significant number of mechanisms have been proposed in an attempt to explain the therapeutic resistance of GBM cells: e.g., the metabolic inactivation of drugs, increased drug efflux, increased DNA repair [ 11 , 12 , 13 ], loss of the potential of microglia to present antigens [ 14 , 15 ], induction of T-cell dysfunction [ 16 , 17 , 18 ], an immunosuppressive tumor microenvironment [ 19 , 20 , 21 ], the blood–brain barrier (BBB), and the role of corticosteroids regularly administered to GBM patients [ 22 ] effectively reducing the BBB permeability by reinforcement of endothelial tight junctions [ 23 ]. In addition, GBM stem-like cells (GSCs) have been proposed in recent years to be responsible for therapeutic resistance and tumor relapse [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…self-renewing cells with stem cell characteristics are referred to as glioblastoma stem-like cells (GSCs) [ 25 , 26 , 27 ]. Whilst the former is sensitive to chemotherapy due to its significantly elevated proliferation rate, the latter is thought to be most resistant to the induction of apoptosis by the established standard therapy, bearing the capacity of tumor initiation as a source of glioma recurrence [ 8 , 13 , 28 , 29 ]. Therefore, novel efficient therapies targeting the resistance of GBM cells, especially GBM stem-like cells, to apoptosis are highly demanded.…”

Section: Introductionmentioning

confidence: 99%

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Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide

et al. 2022

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Current standard adjuvant therapy of glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to therapy resistance. Thus, novel therapeutic approaches are highly demanded. We tested the therapeutic efficacy of the second-generation XPO1 inhibitor Eltanexor using assays for cell viability and apoptosis in GBM cell lines and GBM stem-like cells. For most GBM-derived cells, IC50 concentrations for Eltanexor were below 100 nM. In correlation with reduced cell viability, apoptosis rates were significantly increased. GBM stem-like cells presented a combinatorial effect of Eltanexor with TMZ on cell viability. Furthermore, pretreatment of GBM cell lines with Eltanexor significantly enhanced radiosensitivity in vitro. To explore the mechanism of apoptosis induction by Eltanexor, TP53-dependent genes were analyzed at the mRNA and protein level. Eltanexor caused induction of TP53-related genes, TP53i3, PUMA, CDKN1A, and PML on both mRNA and protein level. Immunofluorescence of GBM cell lines treated with Eltanexor revealed a strong accumulation of CDKN1A, and, to a lesser extent, of p53 and Tp53i3 in cell nuclei as a plausible mechanism for Eltanexor-induced apoptosis. From these data, we conclude that monotherapy with Eltanexor effectively induces apoptosis in GBM cells and can be combined with current adjuvant therapies to provide a more effective therapy of GBM.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide

et al. 2022

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“…Carbonic anhydrase 2 (CA2) belongs to human carbonic anhydrases (CAs), a well-defined group of metal enzymes that catalyze carbon dioxide into bicarbonate [ 28 ]. CA2 functions to regulate ion transport and pH balance, which permeates many biological processes.…”

Section: Discussionmentioning

confidence: 99%

Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma

et al. 2023

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Background Colorectal cancer (CRC), ranking third in cancer prevalence and second in mortality worldwide, is mainly derived from colorectal adenoma (CRA). CRA is a common benign disease in the intestine with rapidly increasing incidence and malignant potential. Therefore, this study aimed to recognize significant biomarkers and original pathogenesis in CRA. Methods Transcriptome data of GSE8671, GSE37364, and GSE15960 were downloaded from the Gene Expression Omnibus (GEO) datasets, and differentially expressed genes (DEGs) were screened. Functional pathways enrichment, protein–protein interaction (PPI) network, stem-correlation analysis, CIBERSORT, risk score and survival analyses were performed. RT-qPCR and immunohistochemical staining were applied to verify our results. Results Screening for significant DEGs in each dataset, we identified 230 robust DEGs, including 127 upregulated and 103 downregulated genes. Functional pathways enrichment showed that these DEGs were distinctly enriched in various tumor-associated pathways, such as growth factor activity, extracellular structure organization, neutrophil activation, and inflammatory response. We filtered out two hub genes via STRING and Modules analysis, including CA2 and HSD11B2. Stem-correlation analysis displayed that hub genes were negatively associated with stem-related genes (Olfm4, CD44, CCND1 and MYC). The CIBERSORT algorithm indicated that Macrophage2, activated mast cells, and Neutrophils promoted CRA progression through inflammation. Survival analysis showed that CA2 and HSD11B2 were positively associated with survival outcomes in CRC. Conclusion Our study has successfully identified the critical role of two core genes in the development and oncogenesis of CRA, which provides novel insight into the underlying pathogenesis, potential biomarkers and therapeutic targets.

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“…Meanwhile, bioinformatics predicted that wogonin could enhance gemcitabine sensitivity of pancreatic cancer by inhibiting AKT2, CCL2, HSP90AA1, PDE5A, and activating PTGS1, BCHE, SERPINB5, CA2, SRC, DGKA, HIF1A, PTGS2, ABCA1, DPYD, AKR1C3. According to the literature, AKT2 (Chen et al, 2012), CCL2 (Monti et al, 2004), HSP90 (Ghadban et al, 2017), CA2 (Zhao et al, 2021), SRC (Lin et al, 2019), HIF1A , ABCA1 (Shen and Yan, 2021), DPYD (Delhorme et al, 2022) and AKR1C3 (Phoo et al, 2021) are associated with drug resistance. The biological process of wogonin sensitization to gemcitabine includes: response to fluid shear stress, cyclooxygenase pathway, response to steroid hormones, positive regulation of transmembrane transport, peptide transport, and ribonucleoside acid metabolism process (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Wogonin increases gemcitabine sensitivity in pancreatic cancer by inhibiting Akt pathway

Zhang

Liu

et al. 2022

Front. Pharmacol.

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Pancreatic cancer has a high degree of malignancy and a low 5-year survival rate, and drug resistance is one of the main factors leading to poor prognosis of pancreatic cancer. Wogonin is a flavonoid drug isolated from Scutellaria baicalensis, which has certain antitumor activity. Hence the purpose of this study was to investigate whether wogonin can be used to enhance the sensitivity of pancreatic cancer to gemcitabine chemotherapy, and investigate its possible sensitization mechanism. In vitro, MTT assay showed that wogonin increased gemcitabine cytotoxicity in gemcitabine-resistant pancreatic cancer cells. In vivo, Wogonin combined with gemcitabine was found to inhibit tumor growth in orthotopic pancreatic cancer mouse model. In order to explore the sensitization mechanism, the differentially expressed genes (DEGs) of the gemcitabine-resistant cell line Panc-1 and the gemcitabine-sensitive cell line Bxpc-3 were screened through the GEO database, and 15 differentially expressed genes were obtained by intersecting with the potential targets of wogonin. Gene Ontology and KEGG enrichment analysis was performed. Bioinformatics results predicted that wogonin promoted pancreatic cancer cell apoptosis by inhibiting protein kinase B (Akt) signaling, thereby enhancing the sensitivity of gemcitabine to Pancreatic cancer. The above results were also verified by flow cytometry and Western blotting experiments. In conclusion, wogonin may enhance the sensitivity of gemcitabine by inhibiting Akt pathway.

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Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells

Cited by 16 publications

References 43 publications

Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide

Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide

Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma

Wogonin increases gemcitabine sensitivity in pancreatic cancer by inhibiting Akt pathway

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