Introduction
Medulloblastoma accounts for 20-25% of all paediatric brain tumours diagnosed worldwide (de Medeiros et al., 2019). Current treatment regimens are effective. However, most options lead to long-term off-target effects. Therefore, the continued development of new, safer treatments for children is paramount. One source of novel therapeutics are those derived from plants, due to decreased side effects compared to synthetic alternatives (Jones et al. 2023). One species which has emerged inrecent years is that of Tripterygium wilfordii and the bioactive compounds it contains. One compound of significant interest is that of celastrol, which has been shown to possess anti-cancer properties (Shi et al., 2020). However, there is limited evidence to showcase its efficacy against medulloblastoma. Therefore, this study sought to determine the cytotoxic and anti-migratory effects of celastrol against medulloblastoma subtypes.
Material and method
The effect of celastrol on medulloblastoma (HD-MB-03, & DAOY) viability was determined using MTT assays. Time-lapse live-cell microscopy was utilised to examine the effect of celastrol on cell morphology, and cell fate profile, in addition to bulk and single-cell migration Fluorescence microscopy was used to measure caspase 3/7 activation [1].
Result and discussion
Celastrol produced concentration and time-dependentdecreases in medulloblastoma (DAOY & HD-MB-03)viability with IC50 values after 72 hours found to be 151and 232 nM respectively. Cell fate profiling showedsignificant increases in death in mitosis (P < 0.0001) butdid not significantly increase cell cycle time (P = 0.132).Morphological analysis highlighted changes indicative ofapoptosis (cell shrinkage & blebbing). Fluorescence microscopy revealed significant increases in caspase 3/7activation (P < 0.001) indicative of apoptotic cell death.Exposure to celastrol significantly decreased bulk cell migration by 50.4 ± 3.8 % (P = 0.0002). Medulloblastoma single-cell migration analysis also revealedsignificant decreases in cell migratory distance and speed (30.4 ± 4.1 %, P < 0.0001).
Conclusion
These data highlight the potential of celastrol as a potential treatment for medulloblastoma through the induction of apoptosis and inhibition of cellular migration, warranting the need for further investigation into the underpinning molecular mechanisms of action.
[1] The study was ethically approved by the University of Salford EthicalReview Board (ID: 10513)
