Restriction lift date: 2028-09-30
Identifying potential synergistic effects of retinoic acid and kinase inhibitors in glioblastoma cells
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Date
2024
Authors
Power, Ellen Mary
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
Every year, approximately 60-80% of malignant primary brain tumours diagnosed are malignant gliomas. Despite significant changes in the treatment of gliomas, the prognosis for a stage 4 glioma, or glioblastoma, is generally poor with a 5-year survival rate of approximately 5%. For this reason, further research is imperative to develop more effective treatments. One possibility under consideration is to induce the terminal differentiation of cancer cells to reduce their proliferation rate and render them more susceptible to chemo- and radiotherapy by targeting both the retinoic acid pathway and the kinase pathways
Retinoic acid (RA), a derivative of vitamin A, has pleiotropic effects in the body, and influences processes such as cell proliferation and differentiation, which are deregulated in tumorigenesis. It has been found to be effective in a number of malignancies where it induces cell differentiation. Although RA was initially proven to induce terminal differentiation in cancer cells in acute promyelocytic leukaemia and hypothesised to be a potential therapeutic agent for a range of cancers, its effects in glioblastoma are more heterogeneous.
The kinase signalling pathways are cascades of essential proteins transducing signals within a cell and playing roles in cell proliferation, survival, differentiation and death. Inhibition of various components of these pathways have shown promise in glioblastoma treatment, however it has been noted that monotherapies trialled in patients are largely ineffective. The relationships between RA and certain kinase pathways have been documented, where RA has been seen to interact with these pathways as well as activate or inhibit them. Thus, combination treatments of RA and various kinase inhibitors could have the potential to reduce cell proliferation in these tumours. Our aim is to investigate if the synergistic effects of RA and kinase inhibitors can act to reduce tumour proliferation. We hypothesise that by combining RA with kinase inhibitors against the p38, PI3K, AKT or ERK1/2 signalling pathways, we will be able to control tumour proliferation, making them more susceptible to conventional therapies.
Using the established A172 glioblastoma cell line, the effects of RA and kinase inhibitors alone or in combination on cell metabolic activity were assessed through a cell mitochondrial assay. Results indicate that a an additive or synergistic effect ++exists between RA and inhibitors of the PI3K pathway, the AKT pathway and the ERK1/2 pathway. The combination treatments targeting these three pathways were found to be more effective in reducing cell metabolic activity in comparison to RA or the inhibitors alone. However, targeting the p38 pathway did not yield significant reduction in proliferation compared to RA or the p38 inhibitor alone. While these findings show promise for more effective therapies for glioblastoma, the mechanisms behind this interaction undoubtedly require further elucidation. More insight into the effect of the inhibition of specific isoforms of these pathways could help in understanding the exact mechanisms behind glioblastoma pathology, and more importantly, its treatment. Although further research is needed, these results highlight a potential therapeutic avenue for patients by simultaneously targeting these pathways.
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Keywords
Glioblastoma treatment , Retinoid , Cell differentiation , Cell proliferation , Kinase , MAPK pathway , PI3K , AKT , p38 , ERK1/2
Citation
Power, E. M. 2024. Identifying potential synergistic effects of retinoic acid and kinase inhibitors in glioblastoma cells. MRes Thesis, University College Cork.