resumo
The interest in palladium(II) compounds as potential new anticancer drugs has increased in recent years, due to their high toxicity and acquired resistance to platinum(II)-derived agents, namely cisplatin. In fact, palladium complexes with biogenic polyamines (e.g., spermine, Pd(2)Spm) have been known to display favorable antineoplastic properties against distinct human breast cancer cell lines. This study describes the in vivo response of triple-negative breast cancer (TNBC) tumors to the Pd(2)Spm complex or to cisplatin (reference drug), compared to tumors in vehicle-treated mice. Both polar and lipophilic extracts of tumors, excised from a MDA-MB-231 cell-derived xenograft mouse model, were characterized through nuclear magnetic resonance (NMR) metabolomics. Interestingly, the results show that polar and lipophilic metabolomes clearly exhibit distinct responses for each drug, with polar metabolites showing a stronger impact of the Pd(II)-complex compared to cisplatin, whereas neither drug was observed to significantly affect tumor lipophilic metabolism. Compared to cisplatin, exposure to Pd(2)Spm triggered a higher number of, and more marked, variations in some amino acids, nucleotides and derivatives, membrane precursors (choline and phosphoethanolamine), dimethylamine, fumarate and guanidine acetate, a signature that may be relatable to the cytotoxicity and/or mechanism of action of the palladium complex. Putative explanatory biochemical hypotheses are advanced on the role of the new Pd(2)Spm complex in TNBC metabolism.
palavras-chave
METABOLOMICS ANALYSIS; DNA-BINDING; TISSUE; CELL; NMR; PALLADIUM(II); CISPLATIN; PROFILES; CHEMOTHERAPY; PLASMA
categoria
Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
autores
Carneiro, TJ; Araujo, R; Vojtek, M; Goncalves-Monteiro, S; de Carvalho, ALMB; Marques, MPM; Diniz, C; Gil, AM
nossos autores
Ana Maria Pissarra Coelho Gil
Professor Associado com Agregação
Ana Rita Araújo Silva
Estudante de doutoramento
Tatiana João Ribeiro Gonçalves Carneiro
Estudante de doutoramentoProjectos
CICECO - Aveiro Institute of Materials (UIDB/50011/2020)
agradecimentos
This research was developed within the scope of the CICECO-Aveiro Institute of Materials, with references UIDB/50011/2020 and UIDP/50011/2020, financed by national funds through the Portuguese Foundation for Science and Technology (FCT/MEC) and when appropriate co-financed by the European Regional Development Fund (FEDER) under the PT2020 Partnership Agreement. This work was also funded by the FCT through UIDB/00070/2020 (A.L.M.d.B.C. and M.P.M.M.), PO-CI-010145-FEDER-0016786, and Centro-01-0145-FEDER-029956 (co-financed by COMPETE 2020, Portugal 2020 and European Community through FEDER). This work also received financial support from PT national funds FCT and Ministerio da Ciencia, Tecnologia e Ensino Superior (MCTES) through the project UIDB/50006/2020 (C.D.). We also acknowledge the Portuguese National NMR Network (PTNMR), supported by FCT funds, as the NMR spectrometer used is part of PTNMR and partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL, and the FCT through PIDDAC); PTNMR and FCT funded PhD grant PTDC/QEQMED/1890/2014 (R.A.). M.V. thanks the FCT and the PhD Program in Medicines and Pharmaceutical Innovation (i3DU) for his PhD grant PD/BD/135460/2017 and T.J.C. thanks FCT for her PhD grant SFRH/BD/145920/2019; both grants were funded by the European Social Fund of the European Union and national funds FCT/MCTES.