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) MDAMB-231 cells to Pd2Sper Show more
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) MDAMB-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.
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