Untargeted Metabolomics Reveals Acylcarnitines as Major Metabolic Targets of Resveratrol in Breast Cancer Cells.

Background/Objectives: Millions of new diagnoses of breast cancer are made each year, with many cases having poor prognoses and limited treatment options, particularly for some subtypes such as triple-negative breast cancer. Resveratrol, a naturally occurring polyphenol, has demonstrated many anticancer properties in breast cancer studies. However, the mechanism of action of this compound remains elusive, although prior evidence suggests that this compound may work through altering cancer cell metabolism. Our objective for the current study was to perform untargeted metabolomics analysis on resveratrol-treated breast cancer cells to identify key metabolic targets of this compound. Methods: MCF-7 and MDA-MB-231 breast cancer cells were treated with varying doses of resveratrol and extracted for mass spectrometry-based untargeted metabolomics. Data preprocessing and filtering of metabolomics data from MCF-7 samples yielded 4751 peaks, with 312 peaks matched to an in-house standards library and 3459 peaks matched to public databases. Results: Pathway analysis in MetaboAnalyst identified significant (p < 0.05) metabolic pathways affected by resveratrol treatment, particularly those involving steroid, fatty acid, amino acid, and nucleotide metabolism. Evaluation of standard-matched peaks revealed acylcarnitines as a major target of resveratrol treatment, with long-chain acylcarnitines exhibiting a 2-5-fold increase in MCF-7 cells and a 5-13-fold increase in MDA-MB-231 cells when comparing the 100 µM treated cells to vehicle-treated cells (p < 0.05, VIP > 1). Notably, doses below 10 µM showed an opposite effect, possibly indicating a biphasic effect of resveratrol due to a switch from anti-oxidant to pro-oxidant effects as dose levels increase. Conclusions: These findings suggest that resveratrol induces mitochondrial metabolic reprogramming in breast cancer cells in a dose-dependent manner. The biphasic response indicates a potential optimal dosage for therapeutic effectiveness. Further research is warranted to explore the mechanisms underlying these metabolic alterations and their implications for precision nutrition strategies in cancer treatment.