Effect of Pd2Spermine on Mice Brain-Liver Axis Metabolism Assessed by NMR Metabolomics

Abstract

Cisplatin (cDDP)-based chemotherapy is often limited by severe deleterious effects (nephrotoxicity, hepatotoxicity and neurotoxicity). The polynuclear palladium(II) compound Pd2Spermine (Pd2Spm) 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 Pd2Spm, 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 Pd2Spm 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 Pd2Spm 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 Pd2Spm as a promising replacement of cDDP.

Pd2Spermine as an Alternative Therapeutics for Cisplatin-Resistant Triple-Negative Breast Cancer

“…Metabolomics has been extensively highlighted as a valuable tool towards the understanding of the interplay between drugs and cellular metabolism in breast cancer . Indeed, metabolomics of CDX mice with TNBC showed that, compared to cDDP, Pd 2 Spm induced (i) pronounced metabolic disturbances in tumor metabolism (energy, membrane, nucleotides, and one-carbon metabolisms), possibly reflecting a different mechanism of action of the Pd­(II) complex, and (ii) an enhanced neuroprotective response of brain, along with lower impact on liver. , Furthermore, Pd 2 Spm administration induced initial metabolic deviations in healthy BALB/c mice, which, however, returned to control levels faster (within 48 h) than with cDDP, namely, in kidney, liver, breast tissue and brain. , This corroborated other reports of lower in vivo toxicity of the Pd­(II) compound, compared to that of cDDP. , …”