Pd2Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer

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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 Pd(2)Spermine(Spm) (a possible alternative to cDDP) compared to cDDP to investigate (i) intrinsic response/resistance mechanisms and (ii) the potential cytotoxic role of Pd(2)Spm. 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). Pd(2)Spm 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 gamma-aminobutyrate/glutathione-mediated antioxidant mechanism.

keywords

SPERMINE; PALLADIUM(II); COMPLEXES; NMR

subject category

Pharmacology & Pharmacy

authors

Carneiro, TJ; de Carvalho, ALMB; Vojtek, M; Laginha, RC; Marques, MPM; Diniz, C; Gil, AM

our authors

foto Ana Maria Pissarra Coelho Gil

Ana Maria Pissarra Coelho Gil

Associate Professor with Aggregation

Groups

G5 - Biomimetic, Biological and Living Materials

Projects

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

Rede Nacional de Ressonância Magnética Nuclear (PTNMR)

acknowledgements

This work was developed within the CICECO-Aveiro Institute of Materials projects UIDB/50011/2020 (10.54499/UIDB/50011/2020), UIDP/50011/2020 (10.54499/UIDP/50011/2020),and LA/P/0006/2020 (10.54499/LA/P/0006/2020), QFMUCyMolecularPhysical Chemistry R&D Unit projects UIDB/00070/2020 (10.54499/UIDB/00070/2020") and UIDP/00070/2020 (10.54499/UIDP/00070/2020), LAQV/REQUIMTEyAssociate Laboratory for Green Chemistry projects 10.54499/LA/P/0008/2020, 10.54499/UIDP/50006/2020, and 10.54499/UIDB/50006/2020,and the A.L.M.B.C. employment contract (10.54499/CEECIND/00069/2017/CP1460/CT0029) financed by national funds through the Portuguese Foundation for Science and Technology (FCT). The authors are grateful to the Portugues eNational NMR Network (PTNMR), supported by FCT funds as the NMR spectrometer used is part of PTNMR and partially supported by Infrastructure Project No. 022161 (cofinanced by FEDER through COMPETE 2020, POCI and PORL, and the FCT through PIDDAC). T.J.C. thanks FCT for her Ph.D. grant SFRH/BD/145920/2019, and M.V. thanks the FCT and the Ph.D. Program in Medicines and Pharmaceutical Innovation (i3DU) for his Ph.D. grant PD/BD/135460/2017; both grants were funded by the European SocialFund of the European Union and national FCT/MCTES funds.

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Publication Details

type
Journal Article
year
2024
journal
JOURNAL OF MEDICINAL CHEMISTRY
volume
67
publisher
AMER CHEMICAL SOC
issn
0022-2623
isbn
1520-4804
issue
8
digital object identifier
10.1021/acs.jmedchem.4c00435
link
hybrid
web of science article identifier
WOS:001199620900001

Journal Metrics (JCR 2019)

Journal Impact Factor
6.205
Journal Impact Factor (5 yrs)
6.521
category normalized journal percentile
95.902

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