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.

keywords

DOSE 2 GY; MOLECULAR-MECHANISMS; IN-VITRO; CISPLATIN; NMR; PLATINUM; MARKERS; PROFILE; SPECTROSCOPY; CHEMOTHERAPY

subject category

Biochemistry & Molecular Biology; Chemistry

authors

Bispo, DSC; Correia, M; Carneiro, TJ; Martins, AS; Reis, AAN; de Carvalho, ALMB; Marques, MPM; Gil, AM

Groups

G5 - Biomimetic, Biological and Living Materials

Projects

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

Metabolite-activated 3D stem cell differentiation into bone (BetterBone)

acknowledgements

This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020 (doi: 10.54499/UIDB/50011/2020), UIDP/50011/2020 (doi: 10.54499/UIDP/50011/2020) and LA/P/0006/2020 (doi:10.54499/LA/P/0006/2020) (AMG), financed by national funds through the FCT/MCTES (PIDDAC). We also acknowledge funds from POCentro, Portugal 2020, and European Community through the FEDER, and by the Portuguese Foundation for Science and Technology (FCT) through LAQV/REQUIMTE FCT UIDB/50006/2020 (C.D.), UIDB/00070/2020 (https://doi.org/10.54499/UIDB/00070/2020) and UIDP/00070/2020 (https://doi.org/10.54499/UIDP/00070/2020) (ALMBC and MPMM), and PO-CI-01-0145-FEDER-0016786, as well as the BetterBone-2022.04286.PTDC (AMG). AMG also acknowledges the Portuguese National NMR Network (RNRMN), supported by Infrastructure Project N-022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC); DSB, TJC and ASM acknowledge FCT/SPQ (SFRH/BD/150655/2020), FCT (SFRH/BD/145920/2019) and FCT/MCTES (SFRH/BD/ 111576/2015) for their PhD grants, respectively.