Bidentate ligands on osmium(VI) nitrido complexes control intracellular targeting and cell death pathways

Abstract

The cellular response evoked by antiproliferating osmium(VI) nitrido compounds of general formula OsN(N^N)Cl3 (N^N = 2,2'-bipyridine 1, 1,10-phenanthroline 2, 3,4,7,8-tetramethyl-1,10-phenanthroline 3, or 4,7-diphenyl-1,10-phenanthroline 4) can be tuned by subtle ligand modifications. Complex 2 induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, 4 evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, 4 is the first osmium compound to induce ER stress in cancer cells.

Figure 1

Structures of the osmium(VI) nitrido complexes under investigation.

Figure 2

RNAi signatures derived from the treatment of Eμ-Myc^{p19arf−/−} lymphoma cells with (a) 2 and (b) 4 at the LD80-90 concentration for each compound.

Figure 3

(a) Graphical representation of the IC₅₀ values of cisplatin, 2, and 4 in the absence and presence of ER stress inhibitor, salubrinal (10 μM). (b & c) Fluorescence microscopy of live A2780 cells incubated at 37 °C for 4 h without (b) and with (c) 4 (10 μM). Both panels contain the blue ER-tracker (5 μM) probe. Scale bar = 9 μm.

Figure 4

Proposed cellular mechanism of action of 2 and 4. Complex 2 targets genomic DNA, whereas 4 induces ER stress.