Response of Osteosarcoma Cell Metabolism to Platinum and Palladium Chelates as Potential New Drugs

Abstract

This paper reports the first metabolomics study of the impact of new chelates Pt2Spm and Pd2Spm (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, Pd2Spm 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.

Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and -Resistant to Cisplatin

“…As previously reported, the initial rate of formazan formation may serve as an indicator of complex I activity and the pyruvate transport rate [37], indicating a disruption of mitochondrial functional activity, conditioning cell metabolism and, therefore, cell viability. Previous metabolomic studies of osteosarcoma in mice in the presence of Pd 2 Spm have highlighted its impact on osteoblastic amino acid metabolism [38], as well as numerous changes in specific amino acids, nucleotides and derivatives; membrane precursors (choline and phosphoethanolamine); dimethylamine; fumarate and guanidine acetate [23]. These data prompt the need for similar metabolomic studies in order to clarify the impact of the currently investigated Pd 3 Spd 2 on TNBC, which may help to understand why different palladium-based chelates (namely, dinuclear with Spm and trinuclear with Spd) exhibit comparable antineoplastic activities towards TNBC, as reported in the present study.…”

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

“…However, the efficacy of Pt­(II) drugs is often hampered by toxicity and acquired resistance. , The latter (defined as tumor relapse within 6 months of initial treatment) is particularly critical in TNBC where intrinsic tumor heterogeneity is associated with increased resistance and relapse, compared to other BC subtypes . These drawbacks of Pt­(II)-based therapy have motivated the search for other metal-based drugs, including palladium [Pd­(II)] complexes. − In particular, the Pd­(II) dinuclear chelate with the biogenic polyamine spermine Pd 2 Spm (Spm, H 2 N­(CH 2 ) 3 NH­(CH 2 ) 4 NH­(CH 2 ) 3 NH 2 ) exhibited promising in vitro antiproliferative, antimigratory, and antiangiogenic properties against the TNBC MDA-MB-231 cell line, along with effective responses in other cancer cell lines, e.g., leukemia, osteosarcoma, oral squamous cells, ovarian, and prostate carcinomas. − In addition, in vivo studies have shown a more favorable biodistribution profile of Pd­(II) in healthy BALB/c mice compared to that of Pt­(II), while exposure of a MDA-MB-231 cell-derived xenograft (CDX) mouse model to Pd 2 Spm resulted in the reduction of tumor size and cell proliferation rate, as well as lower systemic toxicity, compared to cDDP. , Pd 2 Spm also appears to be more selective for TNBC cells, having less deleterious effects on noncancerous breast cells, at least viewed under in vitro conditions . Metabolomics has been extensively highlighted as a valuable tool towards the understanding of the interplay between drugs and cellular metabolism in breast cancer .…”

Impact of Conventional and Potential New Metal-Based Drugs on Lipid Metabolism in Osteosarcoma MG-63 Cells

“…Palladium-based compounds have attracted increasing interest as promising alternatives to platinum drugs, due to the chemical similarity between Pd(II) and Pt(II) ions [14]. In addition, given the ability of linear polyaminic ligands to form stable complexes with both metal ions, polynuclear Pt(II) and Pd(II) chelates with polyamines have been the object of intense research in the last two decades [14][15][16][17][18]. Indeed, biogenic amines such as spermine (H 2 N(CH 2 ) 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 , Spm) have been used as effective coordinating ligands [14], able to bind to more than one metal center and form highly flexible complexes, which allow the formation of long-range intra-and inter-strand crosslinks with DNA.…”