Aleksandra Majchrzak-Celińska1, Julia O Misiorek2, Nastassia Kruhlenia3, Lukasz Przybyl4, Robert Kleszcz3, Katarzyna Rolle2, Violetta Krajka-Kuźniak3. 1. Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland. majchrzakcelinska@ump.edu.pl. 2. Department of Molecular Neurooncology, Institute of Bioorganic Chemistry Polish Academy of Sciences, Poznań, Poland. 3. Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland. 4. Laboratory of Mammalian Model Organisms, Institute of Bioorganic Chemistry Polish Academy of Sciences, Poznań, Poland.
Abstract
BACKGROUND: Glioblastoma (GBM) is the deadliest and the most common primary brain tumor in adults. The invasiveness and proliferation of GBM cells can be decreased through the inhibition of Wnt/β-catenin pathway. In this regard, celecoxib is a promising agent, but other COXIBs and 2,5-dimethylcelecoxib (2,5-DMC) await elucidation. Thus, the aim of this study was to analyze the impact of celecoxib, 2,5-DMC, etori-, rofe-, and valdecoxib on GBM cell viability and the activity of Wnt/β-catenin pathway. In addition, the combination of the compounds with temozolomide (TMZ) was also evaluated. Cell cycle distribution and apoptosis, MGMT methylation level, COX-2 and PGE2 EP4 protein levels were also determined in order to better understand the molecular mechanisms exerted by these compounds and to find out which of them can serve best in GBM therapy. METHODS: Celecoxib, 2,5-DMC, etori-, rofe- and valdecoxib were evaluated using three commercially available and two patient-derived GBM cell lines. Cell viability was analyzed using MTT assay, whereas alterations in MGMT methylation level were determined using MS-HRM method. The impact of COXIBs, in the presence and absence of TMZ, on Wnt pathway was measured on the basis of the expression of β-catenin target genes. Cell cycle distribution and apoptosis analysis were performed using flow cytometry. COX-2 and PGE2 EP4 receptor expression were evaluated using Western blot analysis. RESULTS: Wnt/β-catenin pathway was attenuated by COXIBs and 2,5-DMC irrespective of the COX-2 expression profile of the treated cells, their MGMT methylation status, or radio/chemoresistance. Celecoxib and 2,5-DMC were the most cytotoxic. Cell cycle distribution was altered, and apoptosis was induced after the treatment with celecoxib, 2,5-DMC, etori- and valdecoxib in T98G cell line. COXIBs and 2,5-DMC did not influence MGMT methylation status, but inhibited COX-2/PGE2/EP4 pathway. CONCLUSIONS: Not only celecoxib, but also 2,5-DMC, etori-, rofe- and valdecoxib should be further investigated as potential good anti-GBM therapeutics.
BACKGROUND:Glioblastoma (GBM) is the deadliest and the most common primary brain tumor in adults. The invasiveness and proliferation of GBM cells can be decreased through the inhibition of Wnt/β-catenin pathway. In this regard, celecoxib is a promising agent, but other COXIBs and 2,5-dimethylcelecoxib (2,5-DMC) await elucidation. Thus, the aim of this study was to analyze the impact of celecoxib, 2,5-DMC, etori-,rofe-, and valdecoxib on GBM cell viability and the activity of Wnt/β-catenin pathway. In addition, the combination of the compounds with temozolomide (TMZ) was also evaluated. Cell cycle distribution and apoptosis, MGMT methylation level, COX-2 and PGE2EP4 protein levels were also determined in order to better understand the molecular mechanisms exerted by these compounds and to find out which of them can serve best in GBM therapy. METHODS:Celecoxib, 2,5-DMC, etori-,rofe- and valdecoxib were evaluated using three commercially available and two patient-derived GBM cell lines. Cell viability was analyzed using MTT assay, whereas alterations in MGMT methylation level were determined using MS-HRM method. The impact of COXIBs, in the presence and absence of TMZ, on Wnt pathway was measured on the basis of the expression of β-catenin target genes. Cell cycle distribution and apoptosis analysis were performed using flow cytometry. COX-2 and PGE2EP4 receptor expression were evaluated using Western blot analysis. RESULTS: Wnt/β-catenin pathway was attenuated by COXIBs and 2,5-DMC irrespective of the COX-2 expression profile of the treated cells, their MGMT methylation status, or radio/chemoresistance. Celecoxib and 2,5-DMC were the most cytotoxic. Cell cycle distribution was altered, and apoptosis was induced after the treatment with celecoxib, 2,5-DMC, etori- and valdecoxib in T98G cell line. COXIBs and 2,5-DMC did not influence MGMT methylation status, but inhibited COX-2/PGE2/EP4 pathway. CONCLUSIONS: Not only celecoxib, but also 2,5-DMC, etori-,rofe- and valdecoxib should be further investigated as potential good anti-GBM therapeutics.
Authors: Aleksandra Majchrzak-Celińska; Robert Kleszcz; Anna Stasiłowicz-Krzemień; Judyta Cielecka-Piontek Journal: Int J Mol Sci Date: 2021-10-19 Impact factor: 5.923
Authors: Aleksandra Majchrzak-Celińska; Robert Kleszcz; Elżbieta Studzińska-Sroka; Agnieszka Łukaszyk; Anna Szoszkiewicz; Ewelina Stelcer; Karol Jopek; Marcin Rucinski; Judyta Cielecka-Piontek; Violetta Krajka-Kuźniak Journal: Cells Date: 2022-03-23 Impact factor: 6.600
Authors: Marta Cykowiak; Robert Kleszcz; Małgorzata Kucińska; Jarosław Paluszczak; Hanna Szaefer; Adam Plewiński; Hanna Piotrowska-Kempisty; Marek Murias; Violetta Krajka-Kuźniak Journal: Cells Date: 2021-12-16 Impact factor: 6.600
Authors: Elżbieta Studzińska-Sroka; Aleksandra Majchrzak-Celińska; Przemysław Zalewski; Dominik Szwajgier; Ewa Baranowska-Wójcik; Barbara Kaproń; Tomasz Plech; Marcin Żarowski; Judyta Cielecka-Piontek Journal: Pharmaceuticals (Basel) Date: 2021-12-10