resumo
Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd(2)Spermine (Pd(2)Spm) has emerged as a potential alternative drug, with favorable pharmacokinetic/pharmacodynamic properties. This paper reports on a Nuclear Magnetic Resonance metabolomics study to (i) characterize the response of mice brain and liver to Pd(2)Spm, compared to cDDP, and (ii) correlate brain-liver metabolic variations. Multivariate and correlation analysis of the spectra of polar and lipophilic brain and liver extracts from an MDA-MB-231 cell-derived mouse model revealed a stronger impact of Pd(2)Spm on brain metabolome, compared to cDDP. This was expressed by changes in amino acids, inosine, cholate, pantothenate, fatty acids, phospholipids, among other compounds. Liver was less affected than brain, with cDDP inducing more metabolite changes. Results suggest that neither drug induces neuronal damage or inflammation, and that Pd(2)Spm seems to lead to enhanced brain anti-inflammatory and antioxidant mechanisms, regulation of brain bioactive metabolite pools and adaptability of cell membrane characteristics. The cDDP appears to induce higher extension of liver damage and an enhanced need for liver regeneration processes. This work demonstrates the usefulness of untargeted metabolomics in evaluating drug impact on multiple organs, while confirming Pd(2)Spm as a promising replacement of cDDP.
palavras-chave
CISPLATIN; PHENYLALANINE; MITOCHONDRIAL; SPERMINE; NAD(+); ACID; NEUROINFLAMMATION; PALLADIUM(II); SPECTROSCOPY; INHIBITION
categoria
Biochemistry & Molecular Biology; Chemistry
autores
Carneiro, TJ; 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
Tatiana João Ribeiro Gonçalves Carneiro
Estudante de doutoramentoProjectos
CICECO - Aveiro Institute of Materials (UIDB/50011/2020)
Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)
agradecimentos
This work was developed within the CICECO-Aveiro Institute of Materials project (UIDB/50011/2020, UIDP/50011/2020& LA/P/0006/2020) financed by national funds through the FCT/MEC (PIDDAC). We also acknowledge funds from POCentro, Portugal 2020 and European Community through the FEDER and by the Portuguese Foundation for Science and Technology (FCT) through LAQV/REQUIMTE FCT UIDB/50006/2020 (C.D.), UIDB/00070/2020 (A.L.M.B.d.C. and M.P.M.M.) and POCI-01-0145-FEDER-0016786. We are grateful to 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). 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 Social Fund of the European Union and national FCT/MCTES funds.