Efecto paradójico radiosensibilizante del ácido carnósico en células de melanoma metastásico B16F10una nueva estrategia terapéutica

Résumé

Carnosic acid (CA) is a phenolic diterpene derived from the plant Rosmarinus officinalis, characterised by its high antioxidant activity. Due to its characteristics, it has multiple industrial, cosmetic and nutritional applications. This study aims to evaluate the radioprotective capacity of AC in cells directly exposed to X-rays and in non-irradiated cells that receive signals from X-ray irradiated cells, known as receptor cells of the bystander effect induced by ionising radiation (RIBE). The genoprotective capacity is assessed by genotoxicity assays using in vivo and in vitro micronucleus assays. Radioprotective capacity is assessed by MTT cell survival, in vitro clonogenic, apoptosis and intracellular glutathione assays, comparing radiosensitive cells (normal human prostate epithelium, PNT2) with radioresistant cells (murine metastatic melanoma, B16F10). AC exhibits genoprotective capacity in all cells exposed to ionising radiation (p < 0.001) and in RIBE cells (p < 0.01). In PNT2 cells, AC achieves 97% cell survival after exposure to 20 Gy of X-rays, eliminating 67% of radiation-induced cell death (p < 0.001), decreasing apoptosis (p < 0.001) and increasing the GSH/GSSG ratio (p < 0.01). However, AC administration to B16F10 cells decreased cell survival by 32%, increased cell death by 200% (p < 0.001), and increased cell death by 100% (p < 0.001) in bystander cells (p < 0.01). In addition, it increases cell apoptosis (p < 0.001) and decreases the GSH/GSSG ratio (p < 0.01), expressing a paradoxical radiosensitising effect in these cells. Knowledge of the possible mechanisms of action of substances such as AC in these areas could help to create new treatment pathways that allow the protection of healthy cells and the exclusive damage of neoplastic cells, thus presenting a new desirable strategy for cancer patients in need of radiotherapy.