Selectivity for TP53 signalling drives the mode of action of a highly potent N,O,O-tridentate naphthoquinone-based organoruthenium anticancer drug candidate - in vivo tissue

ABSTRACT: The candidate metallodrug [(3-ethyl-4-oxo-(pyrazolyl)-dihydronaphthalene)(cymene)ruthenium(II)] (1a) was recently shown to exhibit exceptional nanomolar activity in the chemo-resistant SW480 cancer cell line. This study was performed to elucidate the determining parameters of the mode of action of this N,O,O-tridentate organoruthenium compound in vitro and in vivo. For this purpose, four metal(arenes) based on 3-ethyl naphthoquinone (3Et-NQ, a) and 3-morpholine naphthoquinone (3Morph-NQ, b) with ruthenium (1) and osmium (2) were synthesized and characterized. The four compounds were stable in aqueous solution and exhibited ligand- and metal-dependent reactivity towards biological nucleophiles with a selectivity for amino acids over nucleotides at biologically relevant concentrations. Drug effects were elucidated by proteome profiling at subcellular resolution, i.e. by assessing cytoplasmic and nuclear fractions of SW480 cells separately. The ruthenium- and osmium(arene) derivatives containing the 3Et-NQ ligand revealed down-regulated TP53 as a central hub in the perturbation network, connected to down-regulated proliferative MAPK3 signalling. Complex 1a was most active in the SW480 cell line suggesting selectivity for mutant TP53. The 3Et-NQ complexes, particularly 1a, led to tumour inhibition in a CT26 colon carcinoma mouse model, while the 3Morph-NQ complexes were inactive. Tissue proteomic analysis of livers of 1a-treated mice displayed similar stress responses as observed in vitro. Finally, tumour tissues revealed a pronounced down-regulation of Egfr, which is linked to TP53 signalling and confirmed its MoA in vivo.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver, Ct-26 Cell

DISEASE(S): Colon Cancer

SUBMITTER: Christopher Gerner  

LAB HEAD: Christopher Gerner

PROVIDER: PXD059773 | Pride | 2025-08-25

REPOSITORIES: Pride