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)].2H2O or [Ag2(phen)3(mal)].2H2O (mal H2 = malonic acid) resulted in DNA degradation whereas exposure to phen or [Cu(phen)2(mal)].2H2O 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)].2H2O 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.
Coyle
Barry
B
Department of Chemistry, NUI Maynooth, Co. Kildare, Ireland.
Kinsella
Paula
P
McCann
Malachy
M
Devereux
Michael
M
O'Connor
Robert
R
Clynes
Martin
M
Kavanagh
Kevin
K
D000935:Antifungal Agents / Q000009:adverse effects / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D003300:Copper / Q000737:chemistry; D003470:Culture Media; D053938:DNA Fragmentation / Q000187:drug effects / Q000235:genetics; D004271:DNA, Fungal / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008345:Manganese / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D009942:Organometallic Compounds / Q000009:adverse effects / Q000737:chemistry; D010618:Phenanthrolines / Q000009:adverse effects* / Q000737:chemistry; D012834:Silver / Q000737:chemistry; D015003:Yeasts / Q000187:drug effects / Q000235:genetics
D000935:Antifungal Agents; D003470:Culture Media; D004271:DNA, Fungal; D009942:Organometallic Compounds; D010618:Phenanthrolines; D012834:Silver; D008345:Manganese; D003300:Copper