Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition.
International journal of molecular sciences
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Kopanitsa, L., Kopanitsa, M. V., Safitri, D., Ladds, G., & Bailey, D. S. (2021). Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition.. International journal of molecular sciences, 22 (18) https://doi.org/10.3390/ijms22189665
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.
Proliferation, Glioblastoma, Drug combination, Phosphodiesterase inhibitor, Multidrug Resistance-associated Protein 1
Biotechnology and Biological Sciences Research Council (Flexible Talent Mobility Account scheme award)
Brain Tumour Charity (GN-000429)
External DOI: https://doi.org/10.3390/ijms22189665
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330078
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/