Metabolic profiling reveals subtype-specific responses to jerantinine A acetate in breast cancer cells

Jerantinines are natural indole alkaloids with promising anticancer activity in breast cancer cells via mechanisms of action involving tubulin binding and disruption of microtubule dynamics, with growth inhibition values, GI₅₀ < 0.4 µM. However, metabolic responses of different breast cancer phenotypes are not yet understood. In this work, LC-MS-based untargeted metabolomics was used to investigate the response of four selected breast cancer cell lines representing different subtypes (MCF-7, BT-474, MDA-MB-231, and SKBR-3) to treatment with Jerantinine A acetate (JAa). Based on univariate, multivariate and pathway analyses, the results showed metabolic perturbations in amino-acid metabolism, fatty acid oxidation, and redox homeostasis. In breast cancer cells treated with 0.4 µM of JAa for 72 h, the elevated levels of oxidation-related metabolites, including 2-oxoglutarate, butyryl carnitine, propionyl carnitine, and 5-oxo-L-proline, indicated increased oxidative stress. Interestingly, only MCF-7 cells accumulated the antioxidants glutathione and taurine relative to untreated controls, and this response was accompanied by upregulation of wild-type p53 in this cell line. This p53-associated antioxidant capacity offers a mechanistic explanation for the difference in observed GI₅₀ values: GI₅₀ of 0.37 µM in MCF-7 compared to 0.19 µM and 0.14 µM in SKBR-3 and BT-474 cells, respectively, both of which harbour mutant p53 and did not mount an equivalent antioxidant response. These findings provide new insights into the metabolic effects of JAa on breast cancer cells and further support its potential as an anticancer agent. The observed metabolic differences between cell lines may inform future strategies for personalized therapy.