Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition
The paucity of currently available therapies for glioblastoma multiforme requires novel approaches to the treatment of this brain tumour. Disrupting cyclic nucleotide-signalling through phosphodiesterase (PDE) inhibition may be a promising way of suppressing glioblastoma growth. Here, we examined th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/18/9665 |
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| author | Liliya Kopanitsa Maksym V. Kopanitsa Dewi Safitri Graham Ladds David S. Bailey |
| author_facet | Liliya Kopanitsa Maksym V. Kopanitsa Dewi Safitri Graham Ladds David S. Bailey |
| author_sort | Liliya Kopanitsa |
| collection | DOAJ |
| description | The paucity of currently available therapies for glioblastoma multiforme requires novel approaches to the treatment of this brain tumour. Disrupting cyclic nucleotide-signalling through phosphodiesterase (PDE) inhibition may be a promising way of suppressing glioblastoma growth. Here, we examined the effects of 28 PDE inhibitors, covering all the major PDE classes, on the proliferation of the human U87MG, A172 and T98G glioblastoma cells. The PDE10A inhibitors PF-2545920, PQ10 and papaverine, the PDE3/4 inhibitor trequinsin and the putative PDE5 inhibitor MY-5445 potently decreased glioblastoma cell proliferation. The synergistic suppression of glioblastoma cell proliferation was achieved by combining PF-2545920 and MY-5445. Furthermore, a co-incubation with drugs that block the activity of the multidrug resistance-associated protein 1 (MRP1) augmented these effects. In particular, a combination comprising the MRP1 inhibitor reversan, PF-2545920 and MY-5445, all at low micromolar concentrations, afforded nearly complete inhibition of glioblastoma cell growth. Thus, the potent suppression of glioblastoma cell viability may be achieved by combining MRP1 inhibitors with PDE inhibitors at a lower toxicity than that of the standard chemotherapeutic agents, thereby providing a new combination therapy for this challenging malignancy. |
| first_indexed | 2024-03-10T07:36:43Z |
| format | Article |
| id | doaj.art-617bd3f1055e4df0ae2b077301e72368 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T07:36:43Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-617bd3f1055e4df0ae2b077301e723682023-11-22T13:25:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-012218966510.3390/ijms22189665Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 InhibitionLiliya Kopanitsa0Maksym V. Kopanitsa1Dewi Safitri2Graham Ladds3David S. Bailey4IOTA Pharmaceuticals Ltd., St John’s Innovation Centre, Cowley Road, Cambridge CB4 0WS, UKThe Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UKDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UKIOTA Pharmaceuticals Ltd., St John’s Innovation Centre, Cowley Road, Cambridge CB4 0WS, UKThe paucity of currently available therapies for glioblastoma multiforme requires novel approaches to the treatment of this brain tumour. Disrupting cyclic nucleotide-signalling through phosphodiesterase (PDE) inhibition may be a promising way of suppressing glioblastoma growth. Here, we examined the effects of 28 PDE inhibitors, covering all the major PDE classes, on the proliferation of the human U87MG, A172 and T98G glioblastoma cells. The PDE10A inhibitors PF-2545920, PQ10 and papaverine, the PDE3/4 inhibitor trequinsin and the putative PDE5 inhibitor MY-5445 potently decreased glioblastoma cell proliferation. The synergistic suppression of glioblastoma cell proliferation was achieved by combining PF-2545920 and MY-5445. Furthermore, a co-incubation with drugs that block the activity of the multidrug resistance-associated protein 1 (MRP1) augmented these effects. In particular, a combination comprising the MRP1 inhibitor reversan, PF-2545920 and MY-5445, all at low micromolar concentrations, afforded nearly complete inhibition of glioblastoma cell growth. Thus, the potent suppression of glioblastoma cell viability may be achieved by combining MRP1 inhibitors with PDE inhibitors at a lower toxicity than that of the standard chemotherapeutic agents, thereby providing a new combination therapy for this challenging malignancy.https://www.mdpi.com/1422-0067/22/18/9665glioblastomadrug combinationmultidrug resistance-associated protein 1phosphodiesterase inhibitorproliferation |
| spellingShingle | Liliya Kopanitsa Maksym V. Kopanitsa Dewi Safitri Graham Ladds David S. Bailey Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition International Journal of Molecular Sciences glioblastoma drug combination multidrug resistance-associated protein 1 phosphodiesterase inhibitor proliferation |
| title | Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition |
| title_full | Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition |
| title_fullStr | Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition |
| title_full_unstemmed | Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition |
| title_short | Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition |
| title_sort | suppression of proliferation of human glioblastoma cells by combined phosphodiesterase and multidrug resistance associated protein 1 inhibition |
| topic | glioblastoma drug combination multidrug resistance-associated protein 1 phosphodiesterase inhibitor proliferation |
| url | https://www.mdpi.com/1422-0067/22/18/9665 |
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