resumo
This work describes, to our knowledge, the first NMR metabolomics analysis of mice kidney, liver, and breast tissue in response to cisplatin exposure, in search of early metabolic signatures of cisplatin biotoxicity. Balb/c mice were exposed to a single 3.5 mg/kg dose of cisplatin and then euthanized; organs (kidney, liver, breast tissue) were collected at 1, 12, and 48 h. Polar tissue extracts were analyzed by NMR spectroscopy, and the resulting spectra were studied by multivariate and univariate analyses. The results enabled the identification of the most significant deviant metabolite levels at each time point, and for each tissue type, and showed that the largest metabolic impact occurs for kidney, as early as 1 h post-injection. Kidney tissue showed a marked depletion in several amino acids, comprised in an overall 13-metabolites signature. The highest number of changes in all tissues was noted at 12 h, although many of those recovered to control levels at 48 h, with the exception of some persistently deviant tissue-specific metabolites, thus enabling the identification of relatively longer-term effects of cDDP. This work reports, for the first time, early (1-48 h) concomitant effects of cDDP in kidney, liver, and breast tissue metabolism, thus contributing to the understanding of multi-organ cDDP biotoxicity.
palavras-chave
INDUCED NEPHROTOXICITY; CANCER-CELLS; BIOMARKERS; DISCOVERY; SPECTROSCOPY; MECHANISMS; PROFILES; THERAPY; PLASMA; INJURY
categoria
Biochemistry & Molecular Biology
autores
Carneiro, TJ; Araujo, R; Vojtek, M; Goncalves-Monteiro, S; Diniz, C; de Carvalho, ALMB; Marques, MPM; 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 (UID/CTM/50011/2019)
Biochemical Impact of Platinum and Palladium-based Anticancer Agents (BIOIMPACT)
agradecimentos
This research was developed within the scope of the CICECO-Aveiro Institute of Materials, FCT UID/CTM/50011/2019 project (AMG), financed by national funds through the FCT/MCTES and by the Portuguese Foundation for Science and Technology (FCT) through LAQV/REQUIMTE FCT UID/QUI/50006/2019 (CD), UID/MULTI/00070/2019 (MPM), POCI-01-0145-FEDER-0016786 and Centro-01-0145-FEDER-029956 (co-financed by COMPETE 2020, Portugal 2020 and European Community through FEDER). The authors acknowledge further financial support from FCT through PTDC/QEQ-MED/1890/2014, within Project 3599-to Promote Scientific Production and Technological Development as well as the formation of thematic networks (3599-PPCDT)-jointly financed by the European Community Fund FEDER. 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 FCT through PIDDAC). M.V. thanks FCT and PhD Program in Medicines and Pharmaceutical Innovation (i3DU) for PhD grant PD/BD/135460/2017 and T.J.C. thanks FCT for her PhD grant SFRH/BD/145920/2019, both grants funded by the European Social Fund of the European Union and national funds FCT/MCTES.