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Pd2Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer
Tatiana J Carneiro1,2,3, Ana L M Batista de Carvalho2, Martin Vojtek3
1Department of Chemistry and CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal.
Abstract:
Cisplatin (cDDP) resistance is a matter of concern in triple-negative breast cancer therapeutics. We measured the metabolic response of cDDP-sensitive (S) and -resistant (R) MDA-MB-231 cells to Pd2Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/resistance mechanisms and (ii) the potential cytotoxic role of Pd2Spm. Cell extracts were analyzed by untargeted nuclear magnetic resonance metabolomics, and cell media were analyzed for particular metabolites. CDDP-exposed S cells experienced enhanced antioxidant protection and small deviations in the tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid oxidation (proposed cytotoxicity signature). R cells responded more strongly to cDDP, suggesting a resistance signature of activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant antioxidant protection). Pd2Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.
Insights
This study reveals how triple-negative breast cancer cells respond metabolically to cisplatin and a potential alternative, Pd2Spermine. Pd2Spermine shows promise as a potent agent, impacting cancer cell metabolism differently than cisplatin.
Area of Science:
- Biochemistry
- Cancer Biology
- Metabolomics
Background:
- Cisplatin resistance is a significant challenge in treating triple-negative breast cancer.
- Understanding cellular metabolic responses is crucial for developing effective therapeutics.
Purpose of the Study:
- To investigate the metabolic mechanisms of cisplatin sensitivity and resistance in MDA-MB-231 cells.
- To evaluate the cytotoxic potential and metabolic impact of Pd2Spermine as an alternative to cisplatin.
Main Methods:
- Untargeted nuclear magnetic resonance (NMR) metabolomics was employed to analyze cell extracts.
- Metabolites in cell media were quantified to assess cellular responses.
- Comparative analysis was performed on cisplatin-sensitive (S) and -resistant (R) cells.
Main Results:
- Cisplatin-sensitive cells showed enhanced antioxidant protection and altered TCA cycle, pyrimidine metabolism, and lipid oxidation.
- Cisplatin-resistant cells exhibited an activated TCA cycle, altered adenine/uracil metabolism, and phospholipid biosynthesis.
- Pd2Spermine induced significant metabolic changes in both cell types, including amino acid depletion, membrane degradation, and potential antioxidant effects.
Conclusions:
- Cisplatin resistance involves specific metabolic adaptations in triple-negative breast cancer cells.
- Pd2Spermine demonstrates potent cytotoxic effects, distinct from cisplatin, and warrants further investigation.
- Metabolic profiling provides insights into drug response and resistance mechanisms, guiding therapeutic strategies.
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