Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell Line
Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found t...
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2024-04-01
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| Series: | International Journal of Molecular Sciences |
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| author | Kirill A. Kulagin Elizaveta S. Starodubova Pamila J. Osipova Anastasia V. Lipatova Igor A. Cherdantsev Svetlana V. Poddubko Vadim L. Karpov Dmitry S. Karpov |
| author_facet | Kirill A. Kulagin Elizaveta S. Starodubova Pamila J. Osipova Anastasia V. Lipatova Igor A. Cherdantsev Svetlana V. Poddubko Vadim L. Karpov Dmitry S. Karpov |
| author_sort | Kirill A. Kulagin |
| collection | DOAJ |
| description | Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models. We have shown that impaired proteasome function results in increased levels of RNR subunits and increased enzyme activity in yeast. Co-administration of the proteasome inhibitor bortezomib and the RNR inhibitor hydroxyurea was found to significantly reduce the growth rate of <i>S. cerevisiae</i> yeast. Accordingly, the combination of bortezomib and another RNR inhibitor gemcitabine reduced the survival of DBTRG-05MG compared to the HEK293 cell line. Thus, yeast can be used as a simple model to evaluate the efficacy of combinations of proteasome and RNR inhibitors. |
| first_indexed | 2024-04-24T10:42:05Z |
| format | Article |
| id | doaj.art-3660cfcaf8dd44ea97beab5c1ee9a7da |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T10:42:05Z |
| publishDate | 2024-04-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3660cfcaf8dd44ea97beab5c1ee9a7da2024-04-12T13:20:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-04-01257397710.3390/ijms25073977Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell LineKirill A. Kulagin0Elizaveta S. Starodubova1Pamila J. Osipova2Anastasia V. Lipatova3Igor A. Cherdantsev4Svetlana V. Poddubko5Vadim L. Karpov6Dmitry S. Karpov7Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaInstitute of Biomedical Problems of Russian Academy of Sciences, 123007 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaProteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models. We have shown that impaired proteasome function results in increased levels of RNR subunits and increased enzyme activity in yeast. Co-administration of the proteasome inhibitor bortezomib and the RNR inhibitor hydroxyurea was found to significantly reduce the growth rate of <i>S. cerevisiae</i> yeast. Accordingly, the combination of bortezomib and another RNR inhibitor gemcitabine reduced the survival of DBTRG-05MG compared to the HEK293 cell line. Thus, yeast can be used as a simple model to evaluate the efficacy of combinations of proteasome and RNR inhibitors.https://www.mdpi.com/1422-0067/25/7/3977<i>Saccharomyces cerevisiae</i>glioblastoma cell lineproteasomeribonucleotide reductasebortezomibhydroxyurea |
| spellingShingle | Kirill A. Kulagin Elizaveta S. Starodubova Pamila J. Osipova Anastasia V. Lipatova Igor A. Cherdantsev Svetlana V. Poddubko Vadim L. Karpov Dmitry S. Karpov Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell Line International Journal of Molecular Sciences <i>Saccharomyces cerevisiae</i> glioblastoma cell line proteasome ribonucleotide reductase bortezomib hydroxyurea |
| title | Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell Line |
| title_full | Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell Line |
| title_fullStr | Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell Line |
| title_full_unstemmed | Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell Line |
| title_short | Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast <i>Saccharomyces cerevisiae</i> and a Glioblastoma Cell Line |
| title_sort | synergistic effect of a combination of proteasome and ribonucleotide reductase inhibitors in a biochemical model of the yeast i saccharomyces cerevisiae i and a glioblastoma cell line |
| topic | <i>Saccharomyces cerevisiae</i> glioblastoma cell line proteasome ribonucleotide reductase bortezomib hydroxyurea |
| url | https://www.mdpi.com/1422-0067/25/7/3977 |
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