abstract
This paper reports the first metabolomics study of the impact of new chelates Pt(2)Spm and Pd(2)Spm (Spm = Spermine) on human osteosarcoma cellular metabolism, compared to the conventional platinum drugs cisplatin and oxaliplatin, in order to investigate the effects of different metal centers and ligands. Nuclear Magnetic Resonance metabolomics was used to identify meaningful metabolite variations in polar cell extracts collected during exposure to each of the four chelates. Cisplatin and oxaliplatin induced similar metabolic fingerprints of changing metabolite levels (affecting many amino acids, organic acids, nucleotides, choline compounds and other compounds), thus suggesting similar mechanisms of action. For these platinum drugs, a consistent uptake of amino acids is noted, along with an increase in nucleotides and derivatives, namely involved in glycosylation pathways. The Spm chelates elicit a markedly distinct metabolic signature, where inverse features are observed particularly for amino acids and nucleotides. Furthermore, Pd(2)Spm prompts a weaker response from osteosarcoma cells as compared to its platinum analogue, which is interesting as the palladium chelate exhibits higher cytotoxicity. Putative suggestions are discussed as to the affected cellular pathways and the origins of the distinct responses. This work demonstrates the value of untargeted metabolomics in measuring the response of cancer cells to either conventional or potential new drugs, seeking further understanding (or possible markers) of drug performance at the molecular level.
keywords
BIOGENIC POLYAMINES; CISPLATIN; COMPLEXES; PROFILE; NMR; IMPACT; CHEMOTHERAPY; GLUTATHIONE; DOXORUBICIN; SPERMIDINE
subject category
Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
authors
Martins, AS; de Carvalho, ALMB; Marques, MPM; Gil, AM
our authors
Ana Maria Pissarra Coelho Gil
Associate Professor with Aggregation
Ana Sofia da Costa Martins
PhD StudentProjects
CICECO - Aveiro Institute of Materials (UIDB/50011/2020)
acknowledgements
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. MPMM and ALMBC acknowledge support by POCentro, Portugal 2020 and European Community through the FEDER, and by the Portuguese Foundation for Science and Technology (Centro-01-0145-FEDER-029956; UIDB/00070/2020). This work also received financial support from PT national funds (FCT/MCTES, Fundacao para a Ciencia e Tecnologia and Ministerio da Ciencia, Tecnologia e Ensino Superior) through the project UIDB/50006/2020. 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). ASM is grateful for her PhD grant SFRH/BD/111576/2015 funded by the European Social Fund of the European Union and national funds FCT/MCTES.