Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

Abstract

The organometallic “half-sandwich” compound [Os(η6-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-osmium compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.

Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

“…Comparison of flow cytometry data for ROS measurements also supports a difference in the ROS levels in cells responding to 2 compared to FY26. 6 For example, when exposed to FY26, 95% of cells showed high total ROS and high SO levels, compared to the 84% in response to 2. Yet, the levels of total ROS alone were drastically reduced in response to FY26, with only 2.5% of cells in this state, compared to 16% in response to 2.…”

“…Initially, we screened organo-iridium complexes 1 ([Ir(Z 6 in the NCI-60 screen. 8,11 Complex 2 was more active than 1, however both were potent with mean IC 50 values of o1 mM, more potent than the clinical drug CDDP.…”

“…3,4 In contrast, when N,N is an azopyridine ligand, the complexes can cause redox stress in cancer cells and target mitochondrial metabolism. [5][6][7][8] Azopyridine ligands are strong p-acceptors and withdraw electron density from the metal making the M-C bond to the monodentate ligand X (e.g. Cl or I) much less reactive.…”

“…1, suggesting that their activity is closely linked to the azpy-NMe 2 ligand, which is conserved across all three compounds. Moreover since Ir(III) and Os(II) are isoelectronic (outer shell electronic configuration 5d 6 ) and the complexes have similar 3D structures, global charges and probably log p values, it might be expected that they have similar profiles of biological activity. Although the activity of 2 does not correlate with that of any other drugs screened, those of organo-osmium complexes FY12 and FY26 do.…”

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

“…For this reason, the unusual mechanistic properties of organometallic medicinal chemistry are presently the subject of an exponentially growing number of studies [1]. These entities offer inventive strategic approaches [2][3][4][5][6] in terms of optimized space filling, intracellular redox behavior and antitumoral activity, with pharmacophores possessing varied and multiple targeting options that make it possible to counteract the phenomena of resistance to proapoptotic stimuli [7]. To that can be added the variety of available metals [2] and, for the transition elements, the potential availability of several degrees of oxidation.…”