The heterocyclic ruthenium(III) complex KP1019 (FFC14A) causes DNA damage and oxidative stress in colorectal tumor cells.
The Ru(III) complex salt KP1019 induced formation of H2O2 in colorectal tumor cells in a dose-dependent way. It also caused DNA-strand breaks if only weakly doubling tail length to 55.87+/-3.97 microm. Both effects were prevented by 5mM N-acetylcysteine (NAC) which also reduced cytotoxicity (IC(50) 55 vs 30 microM without NAC). Induction of apoptosis was shown by loss of mitochondrial membrane potential in 63.4+/-2.1% of the population and by caspase-dependent cleavage of poly-(ADP-ribose)-polymerase (PARP). Both effects were inhibited by NAC which reduced the population with depolarized mitochondrial membranes to 24.1+/-1.2% and prevented PARP-cleavage indicating a central role oxidative stress in KP1019-induced apoptosis.
Kapitza
Susanne
S
Institute of Cancer Research, Medical University Vienna, Borschkegasse 8a, A 1090 Vienna, Austria.
Jakupec
Michael A
MA
Uhl
Maria
M
Keppler
Bernhard K
BK
Marian
Brigitte
B
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D024161:Collagen Type XI / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D009942:Organometallic Compounds; D018384:Oxidative Stress / Q000187:drug effects*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017975:Ruthenium Compounds / Q000494:pharmacology*
C499319:COL11A2 protein, human; D024161:Collagen Type XI; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000111:Acetylcysteine