Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma
Summary: Pleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive t...
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| Format: | Article |
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Elsevier
2025-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224027524 |
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| author | Josephine Carpentier Marta Freitas Valle Morales Katiuscia Bianchi John Bomalaski Peter Szlosarek Sarah A. Martin |
| author_facet | Josephine Carpentier Marta Freitas Valle Morales Katiuscia Bianchi John Bomalaski Peter Szlosarek Sarah A. Martin |
| author_sort | Josephine Carpentier |
| collection | DOAJ |
| description | Summary: Pleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive therapeutic strategy. We investigated whether combinatory treatment composed of ADI-PEG20 and polyamine inhibitors constitutes a promising novel therapeutic strategy to overcome ADI-PEG20 resistance in mesothelioma patients. Treatment of ADI-PEG20-resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20-resistant cell lines were highly sensitive to the spermidine-analog GC7. We observed a synergistic effect of GC7 and ADI-PEG20 in both ADI-PEG20-sensitive and ADI-PEG20-resistant cell lines. Metabolomic analysis revealed that sensitivity to GC7 is due to inhibition of the Tricarboxylic (TCA) cycle. Significantly, combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. Taken together, we have identified the therapeutic potential of combinatorial treatment of ADI-PEG20 with GC7 for mesothelioma management. |
| format | Article |
| id | doaj-art-83ca83801e1e448b82cbfeab86b4b3c4 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-83ca83801e1e448b82cbfeab86b4b3c42024-12-15T06:16:25ZengElsevieriScience2589-00422025-01-01281111525Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesotheliomaJosephine Carpentier0Marta Freitas1Valle Morales2Katiuscia Bianchi3John Bomalaski4Peter Szlosarek5Sarah A. Martin6Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKPolaris Pharmaceuticals, Inc., San Diego, CA 92121, USACentre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Corresponding authorSummary: Pleural mesothelioma is a highly chemotherapy-resistant cancer. Approximately 50% of mesotheliomas do not express argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme in arginine biosynthesis, making arginine depletion with pegylated arginine deiminase (ADI-PEG20) an attractive therapeutic strategy. We investigated whether combinatory treatment composed of ADI-PEG20 and polyamine inhibitors constitutes a promising novel therapeutic strategy to overcome ADI-PEG20 resistance in mesothelioma patients. Treatment of ADI-PEG20-resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20-resistant cell lines were highly sensitive to the spermidine-analog GC7. We observed a synergistic effect of GC7 and ADI-PEG20 in both ADI-PEG20-sensitive and ADI-PEG20-resistant cell lines. Metabolomic analysis revealed that sensitivity to GC7 is due to inhibition of the Tricarboxylic (TCA) cycle. Significantly, combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. Taken together, we have identified the therapeutic potential of combinatorial treatment of ADI-PEG20 with GC7 for mesothelioma management.http://www.sciencedirect.com/science/article/pii/S2589004224027524Natural sciencesBiological sciencesSystems biologyCancer systems biologyCancer |
| spellingShingle | Josephine Carpentier Marta Freitas Valle Morales Katiuscia Bianchi John Bomalaski Peter Szlosarek Sarah A. Martin Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma iScience Natural sciences Biological sciences Systems biology Cancer systems biology Cancer |
| title | Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma |
| title_full | Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma |
| title_fullStr | Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma |
| title_full_unstemmed | Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma |
| title_short | Overcoming resistance to arginine deprivation therapy using GC7 in pleural mesothelioma |
| title_sort | overcoming resistance to arginine deprivation therapy using gc7 in pleural mesothelioma |
| topic | Natural sciences Biological sciences Systems biology Cancer systems biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224027524 |
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