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Prodigiosin in glioblastoma: mechanistic pharmacology and rationale for its development as a radiosensitiser
1School of Biological Sciences, University of Manchester, Manchester, United Kingdom.
Background:
Glioblastoma (GBM) exhibits marked resistance to radiotherapy due to hypoxia, metabolic adaptation, enhanced DNA damage response, and the persistence of glioma stem cells (GSCs). Radiosensitisers have therefore become a key therapeutic focus, yet clinically effective agents remain limited.
Objective:
This narrative review synthesises current knowledge on GBM radioresistance mechanisms and evaluates prodigiosin (PG)-a marine-derived tripyrrole pigment-as a potential radiosensitiser, based on its diverse antitumour mechanisms.
Content:
PG demonstrates multifaceted cytotoxic activity in GBM through cytosolic acidification, mitochondrial destabilisation, ER stress and autophagy-associated cell death, DNA intercalation and copper-dependent oxidative cleavage, modulation of MAPK and PI3K-Akt signalling, and inhibition of proliferative and survival pathways. These actions intersect with major determinants of radioresistance, including DNA repair efficiency, ROS adaptation, GSC maintenance and checkpoint recovery. We outline mechanistic hypotheses for PG-radiation synergy, discuss delivery challenges such as BBB penetration, and propose a structured roadmap for in vitro, in vivo and translational investigation.
Conclusion:
Although no studies have directly evaluated PG in combination with radiation, its biological profile supports strong theoretical potential as a radiosensitiser. This review integrates current evidence into a mechanistic pharmacology framework and outlines a structured experimental roadmap for evaluating prodigiosin as a marine-derived radiosensitiser in preclinical drug discovery.
Insights
Prodigiosin, a marine pigment, shows potential as a radiosensitiser for glioblastoma (GBM) by targeting multiple radioresistance mechanisms. Further research is needed to explore its combination with radiation therapy for improved GBM treatment.
Area of Science:
- Oncology
- Pharmacology
- Marine Biology
Background:
- Glioblastoma (GBM) is highly resistant to radiotherapy due to factors like hypoxia, metabolic adaptation, DNA repair, and glioma stem cells (GSCs).
- Limited availability of clinically effective radiosensitisers necessitates the exploration of novel therapeutic agents.
Purpose of the Study:
- To review GBM radioresistance mechanisms and evaluate prodigiosin (PG) as a potential radiosensitiser.
- To explore PG's antitumour mechanisms and their relevance to overcoming GBM radioresistance.
Main Methods:
- Narrative review synthesizing current knowledge on GBM radioresistance.
- Evaluation of prodigiosin's cytotoxic activities and known antitumour mechanisms.
- Mechanistic pharmacology framework to hypothesize PG-radiation synergy.
Main Results:
- Prodigiosin exhibits multifaceted cytotoxic activity in GBM, including inducing cell death, DNA damage, and modulating key signaling pathways.
- PG's mechanisms intersect with critical radioresistance determinants like DNA repair, ROS adaptation, and GSC maintenance.
- Theoretical potential for PG-radiation synergy exists, though direct studies are lacking.
Conclusions:
- Prodigiosin demonstrates significant theoretical potential as a radiosensitiser for glioblastoma.
- Further preclinical investigation, including BBB penetration studies, is warranted.
- A structured roadmap for evaluating PG in combination with radiation is proposed for drug discovery.