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Introduction: Glioblastoma multiforme is the most malignant cancer in the human body with limited treatment options, in which Temozolomide (TMZ) is the conventional chemotherapeutic agent (CA) often prescribed for this condition. Fatty acids (FAs) per se, including polyunsaturated fatty acids (PUFAs), have been prescribed as adjuvants molecules for general cancer treatment. However, little is known about potential interactions between these lipids and the CAs. TMZ was combined with different FAs to access the nature of the interactions between these compounds. Methods: Two in vitro barrier models of the gut-brain axis (GBA) and the blood-brain barrier (BBB) were used. In each of them, 2-hydroxyoleic acid (2-OHOA); gamma-linolenic acid (GLA); and fish oil (FO) which contains both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were used as treatments. Results: In both GBA and BBB models, the combination of TMZ with each FA elicited antagonistic effects, interfering with the transepithelial electrical resistance (TEER) and producing less or no response in the inhibition of T98G cell proliferation. This was associated with alterations in cell morphology, β-catenin and E-cadherin protein expression, and induction of lipid droplets. Conclusion: Using our in vitro barrier models, we concluded that the FA might negatively interfere with TMZ`s cytotoxic effect. On the other hand, TMZ also may play a negative role in the antitumor action of specific FA like GLA or 2-OHOA, as observed in the GBA model. These results call into question the clinical utilization of these FA as nutritional adjuvants for patients under the use of TMZ.

In vitro Influence of Different Fatty Acids on the Pharmacological Effect of Temozolomide