Falcone Isabella G, Rushing Blake R
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA.
Metabolites. 2025 Apr 5;15(4):250. doi: 10.3390/metabo15040250.
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. 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. Pathway analysis in MetaboAnalyst identified significant ( < 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 ( < 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. 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.
每年都有上百万例乳腺癌被新诊断出来，许多病例预后较差且治疗选择有限，尤其是对于某些亚型，如三阴性乳腺癌。白藜芦醇是一种天然存在的多酚，在乳腺癌研究中已显示出许多抗癌特性。然而，尽管先前有证据表明该化合物可能通过改变癌细胞代谢起作用，但其作用机制仍不清楚。我们当前研究的目的是对白藜芦醇处理的乳腺癌细胞进行非靶向代谢组学分析，以确定该化合物的关键代谢靶点。MCF-7和MDA-MB-231乳腺癌细胞用不同剂量的白藜芦醇处理，并进行基于质谱的非靶向代谢组学提取。对MCF-7样本的代谢组学数据进行数据预处理和过滤，得到4751个峰，其中312个峰与内部标准库匹配，3459个峰与公共数据库匹配。MetaboAnalyst中的通路分析确定了受白藜芦醇处理影响的显著（<0.05）代谢通路，特别是那些涉及类固醇、脂肪酸、氨基酸和核苷酸代谢的通路。对标准匹配峰的评估显示，酰基肉碱是白藜芦醇处理的主要靶点，将100μM处理的细胞与溶媒处理的细胞进行比较时，长链酰基肉碱在MCF-7细胞中增加2至5倍，在MDA-MB-231细胞中增加5至13倍（<0.05，VIP>1）。值得注意的是，低于10μM的剂量显示出相反的效果，这可能表明白藜芦醇由于随着剂量水平增加从抗氧化作用转变为促氧化作用而具有双相效应。这些发现表明白藜芦醇以剂量依赖的方式诱导乳腺癌细胞中的线粒体代谢重编程。双相反应表明存在治疗有效性的潜在最佳剂量。有必要进一步研究以探索这些代谢改变的潜在机制及其对癌症治疗中精准营养策略的影响。
