Induction of apoptosis in yeast and mammalian cells by exposure to 1,10-phenanthroline metal complexes

1, 10-Phenanthroline (phen) and metal-phen complexes display fungicidal and fungiststic activity, disrupt mitochondrial function and induce oxidative stress. We have examined the effect of these drugs on the structure of yeast and mammalian cell organelles and the integrity of cellular DNA. Exposure of Candida albicans to [Mn(phen)(2)(mal)].2H(2)O or [Ag-2(phen)(3)(mal)].2H(2)O (mal H-2 malonic acid) resulted in DNA degradation whereas exposure to phen or [Cu(phen)(2)(mal)].2H(2)O did not. All drugs induced extensive changes to the internal structure of yeast cells including retraction of the cytoplasm, nuclear fragmentation and disruption of the mitochondrion. In the case of cultured mammalian cells [Cu(phen)(2)(mal)].2H(2)O induced apoptosis as evidenced by the ladder pattern of DNA fragments following gel electrophoresis and also the blebbing of the cell membrane. The other drugs produced non-specific DNA degradation in mammalian cells. In conclusion, phen and metal-phen complexes have the potential to induce apoptosis in fungal and mammalian cells. Given their distinct mode of action compared to conventional anti-fungal drugs, phen and metal-phen complexes may represent a novel group of anti-fungal agents for use either in combination with existing drugs or in cases where resistance to conventional drugs has emerged. (C) 2003 Elsevier Ltd. All rights reserved.