Prodigiosin in glioblastoma: mechanistic pharmacology and rationale for its development as a radiosensitiser.

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.