期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 19, 页码 -出版社
MDPI
DOI: 10.3390/ijms221910775
关键词
platinum(II); palladium(II); spermine; cisplatin; human triple-negative breast cancer; xenografts; mice; NMR; metabolomics
资金
- national funds through the Portuguese Foundation for Science and Technology (FCT/MEC) [UIDB/50011/2020, UIDP/50011/2020]
- European Regional Development Fund (FEDER)
- FCT [UIDB/00070/2020, PO-CI-010145-FEDER-0016786, Centro-01-0145-FEDER-029956, PTDC/QEQMED/1890/2014]
- COMPETE 2020
- Portugal 2020
- European Community through FEDER
- PT national funds FCT
- Ministerio da Ciencia, Tecnologia e Ensino Superior (MCTES) [UIDB/50006/2020]
- FCT funds, as the NMR spectrometer used is part of PTNMR [022161]
- FEDER through COMPETE 2020, POCI and PORL
- FCT through PIDDAC
- PTNMR
- PhD Program in Medicines and Pharmaceutical Innovation (i3DU) - European Social Fund of the European Union [PD/BD/135460/2017]
- FCT - European Social Fund of the European Union [SFRH/BD/145920/2019]
- national funds FCT/MCTES
- Fundação para a Ciência e a Tecnologia [SFRH/BD/145920/2019, PD/BD/135460/2017, UIDB/00070/2020] Funding Source: FCT
Interest in palladium(II) compounds as potential new anticancer drugs has increased due to their high toxicity and acquired resistance to platinum(II)-derived agents, such as cisplatin. This study examines the in vivo response of TNBC tumors to a Pd(2)Spm complex compared to cisplatin, showing distinct impacts on polar metabolites but not on tumor lipophilic metabolism. The results suggest that the Pd(2)Spm complex triggers more variations in certain metabolites related to cytotoxicity and may have a distinct mechanism of action in TNBC metabolism.
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.
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