Key result
Doxorubicin plus 5-fluorouracil reduces critical metabolites vs individual treatments in a TNBC mouse model.
Why the study?
Triple-negative breast cancer poses major clinical challenges due to aggressive behavior and limited treatment options, prompting investigation into molecular metabolic alterations induced by doxorubicin and 5-fluorouracil.
The study highlights TNBC's metabolic alterations to chemotherapeutics, identifying potential biomarkers like L-fucose and beta-alanine, and provides insights for improving treatment strategies.
Hypothesis-generating for TNBC metabolic biomarkers; leaves open clinical translation of combination chemotherapy effects.
Background: Breast cancer is one of the most prevalent malignancies and a leading cause of death among women worldwide. Among its subtypes, triple-negative breast cancer (TNBC) poses significant clinical challenges due to its aggressive behavior and limited treatment options. This study aimed to investigate the effects of doxorubicin (DOX) and 5-fluorouracil (5-FU) as monotherapies and in combination using an established MDA-MB-231 xenograft model in female BALB/C nude mice employing advanced metabolomics analysis to identify molecular alterations induced by these treatments. Methods: We conducted comprehensive plasma and tumor tissue sample profiling using ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). Results: Each treatment group exhibited unique metabolic profiles in plasma and tumor analysis. Univariate and enrichment analyses identified alterations in metabolic pathways. The combination treatment of DOX + 5-FU induced the most extensive metabolic alterations disrupting key pathways including purine, pyrimidine, beta-alanine, and sphingolipid metabolism. It significantly reduced critical metabolites such as guanine, xanthine, inosine, L-fucose, and sphinganine, demonstrating enhanced cytotoxic effects compared to individual treatments. The DOX treatment uniquely increased ornithine levels, while 5-FU altered sphingolipid metabolism, promoting apoptosis. Significance: study highlights TNBC's metabolic alterations to chemotherapeutics, identifying potential biomarkers like L-fucose and beta-alanine, and provides insights for improving treatment strategies.
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Hassanein et al. (2025) studied Triple-negative breast cancer (TNBC). Doxorubicin (DOX) and 5-fluorouracil (5-FU) combination therapy vs. DOX monotherapy and 5-FU monotherapy was evaluated on Metabolic alterations in plasma and tumor tissue. Combination treatment of doxorubicin and 5-fluorouracil induced extensive metabolic alterations, significantly reducing critical metabolites compared to individual treatments in a TNBC mouse model.
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