Action of Carnosic Acid Against Melanoma: A Strategy for Selective Radiosensitization with Protection of Non-Tumoral Cells

Carnosic acid (CA) is a phenolic diterpene with high antioxidant activity that supports its radioprotective capacity. This study aims to determine whether the radiosensitizing effect of CA established in B16F10 melanoma cells also occur in other mela-nin-producing cells. Cell survival analysis, apoptosis, intracellular glutathione levels, and cell cycle progression were evaluated by comparing radiosensitive cells (PNT2) with radioresistant melanin-producing cells (MELAN A, SK-MEL-1 and B16F10). In PNT2 cells, CA exhibited radioprotective capacity, with 100% cell survival after expo-sure to 20 Gy of X-rays (p < 0.001), decreasing apoptosis (p < 0.001) and increasing the GSH/GSSH ratio (p < 0.01), without significant modification in cell cycle progression. However, the administration of CA to irradiated cells failed to show radioprotective capacity in MELAN A and SK-MEL-1 cells, it even doubled cell death in B16F10 cells (p < 0.001); did not modify cell apoptosis, nor prevent a decrease in the GSH/GSSG ratio and intensify the modifications in the cell cycle induced by ionizing radiation. All of these led to a loss of radioprotective capacity in the melanin producing cells (MELAN A and SK-MEL-1) and even induced a radiosensitizing effect in B16F10 cells. Understanding the mechanisms of action of substances such as CA could promote new applications that protect healthy cells and exclusively damage neoplastic cells when both are present within the same irradiated volume in cancer patients requiring radiotherapy.