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Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor

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posted on 2024-11-16, 03:45 authored by Martin Engel, Yi Sing Gee, Dale Cross, Alan MaccaroneAlan Maccarone, Benjamin Heng, Amy HulmeAmy Hulme, Grady Smith, Gilles Guillemin, Brett Stringer, Christopher HylandChristopher Hyland, Lezanne OoiLezanne Ooi
Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine‐specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual‐action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD1 inhibitor 2‐phenylcyclopropylamine with the glutathione scavenger para‐quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two‐dimensional and three‐dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double‐hit hypothesis of potentially targeting LSD1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers.

Funding

Supporting a friend: the role of the molecular scaffold CoREST family in chromatin regulation and neuroprotection

National Health and Medical Research Council

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Neuronal membranes and connections in dementia: targets for intervention

National Health and Medical Research Council

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History

Citation

Engel, M., Gee, Y., Cross, D., Maccarone, A., Heng, B., Hulme, A., Smith, G., Guillemin, G. J., Stringer, B. W., Hyland, C. J. T. & Ooi, L. (2019). Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor. Journal of Neurochemistry, 149 535-550.

Journal title

Journal of neurochemistry

Volume

149

Issue

4

Pagination

535-550

Language

English

RIS ID

133217

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