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

Abstract

This work investigated the mechanisms of action of conventional drugs, cisplatin and oxaliplatin, and the potentially less deleterious drug Pd2Spermine (Spm) and its Pt(II) analog, against osteosarcoma MG-63 cells, using nuclear-magnetic-resonance metabolomics of the cellular lipidome. The Pt(II) chelates induced different responses, namely regarding polyunsaturated-fatty-acids (increased upon cisplatin), suggesting that cisplatin-treated cells have higher membrane fluidity/permeability, thus facilitating cell entry and justifying higher cytotoxicity. Both conventional drugs significantly increased triglyceride levels, while Pt2Spm maintained control levels; this may reflect enhanced apoptotic behavior for conventional drugs, but not for Pt2Spm. Compared to Pt2Spm, the more cytotoxic Pd2Spm (IC50 comparable to cisplatin) induced a distinct phospholipids profile, possibly reflecting enhanced de novo biosynthesis to modulate membrane fluidity and drug-accessibility to cells, similarly to cisplatin. However, Pd2Spm differed from cisplatin in that cells had equivalent (low) levels of triglycerides as Pt2Spm, suggesting the absence/low extent of apoptosis. Our results suggest that Pd2Spm acts on MG-63 cells mainly through adaptation of cell membrane fluidity, whereas cisplatin seems to couple a similar effect with typical signs of apoptosis. These results were discussed in articulation with reported polar metabolome adaptations, building on the insight of these drugs’ mechanisms, and particularly of Pd2Spm as a possible cisplatin substitute.

Cell Metabolomics to Guide the Design of Metal-Based Compounds

“…To our knowledge, only two metabolomic studies compared the metabolic effects induced by the three clinically approved Pt(II)-based drugs. The group of Ana Gill compared the effects of cisplatin and oxaliplatin in human osteosarcoma cells [39], while our research group compared the effects of cisplatin, carboplatin, and oxaliplatin in human ovarian cancer cells [24]. Interestingly, the presence of different Pt(II)-based ligands in the square planar geometry of these molecules does not significantly affect the patterns of metabolomic alterations, but only seems to modulate the extent of the changes.…”

“…Due to the high similarity between Pt(II) and Pd(II), palladium chelates are among the molecules that have drawn increasing interest. In particular, the cellular effects of Pd(II)-spermine and Pt(II)-spermine complexes have been extensively characterized via 1 H NMR metabolomics in osteosarcoma cells, also in comparison to cisplatin and oxaliplatin [37][38][39]41]. In this case, it is the different metal center that modulates the extent of the typical changes in the cell metabolome.…”

“…• Pt(II)Spermine• Cisplatin• Oxaliplatin[39] • Pd(II)Spermine Human osteosarcoma MG-63 cells1 H NMR Lipidic extracts (m/c/w) IC50 at 24 h Inorganics 2024, 12, x FOR PEER REVIEW 7 of 16…”