Jacaric Acid Empowers RSL3-Induced Ferroptotic Cell Death in Two- and Three-Dimensional Breast Cancer Cell Models

Area of Science:

• Oncology
• Biochemistry
• Cancer Therapeutics

Background:

• Ferroptosis, a form of regulated cell death, is a promising strategy against therapy-resistant cancers.
• Lipid peroxidation is a key trigger for ferroptosis, suggesting that enhancing cancer cell susceptibility to it is a viable therapeutic approach.
• Conjugated linolenic acids (CLnAs) are highly peroxidisable fatty acids that can increase susceptibility to ferroptosis.

Purpose of the Study:

• To evaluate jacaric acid (JA), a plant-derived CLnA, as a ferroptosis inducer in breast cancer.
• To assess JA as a monotherapy and in combination with the ferroptosis inducer RSL3.
• To investigate the mechanism of JA-induced ferroptosis in 2D and 3D breast cancer models.

Main Methods:

• Treatment of 2D and 3D breast cancer cell models with jacaric acid (JA) and RAS-selective lethal 3 (RSL3).
• Assessment of cell viability and lipid peroxidation levels.
• Analysis of anti-ferroptotic gene expression.

Main Results:

• JA treatment significantly reduced breast cancer cell viability across all models.
• JA-induced cell death was primarily driven by lipid peroxidation due to JA incorporation into cellular lipids.
• JA synergistically enhanced RSL3 cytotoxicity in both 2D and 3D models, an effect also observed with punicic acid.

Conclusions:

• Plant-derived CLnAs like JA can be effectively used to induce ferroptosis in breast cancer cells.
• JA exploits cancer's increased fatty acid uptake, turning it into a vulnerability by creating a highly peroxidisable environment.
• Combining JA with RSL3 enhances therapeutic efficacy, potentially reducing drug dosage and side effects.