Potential interactions between metal-based phenanthroline drugs and the unfolded protein response endoplasmic reticulum stress pathway

Abstract The unfolded protein response has recently been implicated as a mechanism by which 1,10-phenanthroline-containing coordination compounds trigger cell death. We explored the interaction of two such compounds—one containing copper and one containing manganese—with endoplasmic reticulum (ER) stress. Pretreatment with anisomycin significantly enhanced the cytotoxic activity of both metal-based compounds in A2780, but only the copper-based compound in A549 cells. The effects of pretreatment with tunicamycin were dependent on the nature of the metal center in the compounds. In A2780 cells, the cytotoxic action of the copper compound was reduced by tunicamycin only at high concentration. In contrast, in A549 cells the efficacy of the manganese compound cells was reduced at all tested concentrations. Intriguingly, some impact of free 1,10-phenanthroline was also observed in A549 cells. These results are discussed in the context of the emerging evidence that the ER plays a role in the cytotoxic action of 1,10-phenanthroline-based compounds.