Paradoxical Radiosensitizing Effect of Carnosic Acid on B16F10 Metastatic Melanoma Cells: A New Treatment Strategy

Abstract

Carnosic acid (CA) is a phenolic diterpene characterized by its high antioxidant activity; it is used in industrial, cosmetic, and nutritional applications. We evaluated the radioprotective capacity of CA on cells directly exposed to X-rays and non-irradiated cells that received signals from X-ray treated cells (radiation induced bystander effect, RIBE). The genoprotective capacity was studied by in vivo and in vitro micronucleus assays. Radioprotective capacity was evaluated by clonogenic cell survival, MTT, apoptosis and intracellular glutathione assays comparing radiosensitive cells (human prostate epithelium, PNT2) with radioresistant cells (murine metastatic melanoma, B16F10). CA was found to exhibit a genoprotective capacity in cells exposed to radiation (p < 0.001) and in RIBE (p < 0.01). In PNT2 cells, considered as normal cells in our study, CA achieved 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/GSSH ratio (p < 0.01). However, the administration of CA to B16F10 cells decreased cell survival by 32%, increased cell death by 200% (p < 0.001) compared to irradiated cells, and increased cell death by 100% (p < 0.001) in RIBE bystander cells (p < 0.01). Furthermore, it increased apoptosis (p < 0.001) and decreased the GSH/GSSG ratio (p < 0.01), expressing a paradoxical radiosensitizing effect in these cells. Knowing the potential mechanisms of action of substances such as CA could help to create new applications that would protect healthy cells and exclusively damage neoplastic cells, thus presenting a new desirable strategy for cancer patients in need of radiotherapy.

Spice-Derived Phenolic Compounds: Potential for Skin Cancer Prevention and Therapy

“…Based on these results, it is suggested that the inhibition of EMT might be a key factor contributing to the reduced cell migration in B16F10 cells treated with CrA [376]. In a recent study by Alcaraz et al (2022), CrA was identified as a potent radiosensitizing agent [377]. The research demonstrated that when B16F10 melanoma cells were exposed to X-ray irradiation, CrA significantly reduced their cell survival, indicating its potential to enhance the effectiveness of radiotherapy in treating melanoma.…”

“…In addition, RA also enhanced the sensitivity of melanoma cells to cisplatin [241]. Additionally, the radiosensitizing effect of RA in melanoma B16F10 cells was documented and this effect can be associated with decreased GSH-dependent protection against oxidative stress [242,243]. Moreover, oral administration of RA completely prevented DMBA-induced carcinogenesis in Swiss albino mice.…”