Bioactive Isomers of Conjugated Linoleic Acid Inhibit the Survival of Malignant Glioblastoma Cells But Not Primary Astrocytes

Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid (LA), which is reported as anti‐proliferative against glioblastoma (GBM). However, its toxicity on primary astrocytes remains unclear. The aim of this study is to evaluate the selectivity of bioactive isomers (CLA1) toward GBM and elucidate the possible mechanism of cytotoxicity. The findings show that CLA1 (a 50:50 mixture of cis‐9,trans‐11 CLA and trans‐10,cis‐12 CLA) decreases the viability of GBM but not the viability of normal astrocytes. In contrast, linoleic acid (LA) and CLA2 (a 25:25:50 mixture of cis‐9,trans‐11 CLA, trans‐10,cis‐12 CLA, and trans,trans‐CLA) does not modify the GBM viability, indicating that positional and geometric isomerism is relevant for CLA toxicity. Mitochondrial dysfunction and reactive oxygen species are involved in the toxic effects induced by CLA1 on transformed cells but not in astrocytes, while cell membrane integrity is not altered. In conclusion, these data suggest that CLA represents a possible adjuvant in the GBM therapy since it does not induce adverse side effects on primary astrocytes. Practical Applications: The practical applications of the present work are related to the potential and selective applications of CLA1 as adjuvant in the anti‐glioma therapy, studying firstly the effect of chemical structures derived from LA conversion to CLA, and the consequent mechanism of action induced by synthetic bioactive CLA isomers. The implication of this research is providing evidences that support the potential use of antitumoral drugs in combination with CLA1: 1) as an efficient vehicle for antitumoral drugs crossing the blood brain barrier in order to increase their bioavailability and destroy the tumor cells and 2) CLA1 per se promotes the low survival of glioma as is shown in the research. Bioactive Conjugated linoleic acid (CLA) isomers mixture (CLA1) decreases the viability of glioma C6 cells in comparison to its healthy counterpart, the astrocytes, which survive in presence of increasing concentrations of CLA1. That difference conducts to explore how CLA1 can act upon glioma C6 cells, showing that CLA1 increases the ROS concentration, decreases the MMP which affect the mitochondrion function and promoting apoptosis. In this study, the activation of the PPARγ receptor is not observed, suggesting that these actions are PPARγ receptor independent mechanism. Bioactive Conjugated linoleic acid (CLA) isomers mixture (CLA1)