I. Krueger et al., Nickel(II) increases the sensitivity of V79 Chinese hamster cells towards cisplatin and transplatin by interference with distinct steps of DNA repair, CARCINOGENE, 20(7), 1999, pp. 1177-1184
Nickel compounds are carcinogenic to humans and to experimental animals. In
contrast to their weak mutagenicity; they have been shown previously to in
crease UV-induced cytotoxicity and mutagenicity and to interfere with the r
epair of UV-induced DNA lesions by disrupting DNA-protein interactions invo
lved in DNA damage recognition. In the present study me applied cisplatin,
transplatin and mitomycin C to investigate whether these enhancing effects
and DNA repair inhibition are also relevant for other DNA damaging agents,
Nickel(II) at non-cytotoxic concentrations of 50 mu M and higher caused a p
ronounced increase in cisplatin-, transplatin- and mitomycin C-induced cyto
toxicity, which was neither due to an altered uptake of cisplatin or transp
latin nor to an increase in DNA adduct formation, However, nickel(II) inhib
ited the repair of cisplatin- and transplatin-induced DNA lesions, In combi
nation with transplatin, it decreased the incision frequency, indicating th
at the DNA damage recognition/incision step during nucleotide excision repa
ir is affected in general by nickel(II), In support of this, concentrations
as low as 10 mu M nickel(II) decreased binding of the xeroderma pigmentosu
m complementation group A protein to a cisplatin-damaged oligonucleotide, W
hen combined with cisplatin, the incision frequency was affected only margi
nally, while nickel(II) led to a marked accumulation of DNA strand breaks,
indicating an inhibition of the polymerization/ligation step of the repair
process. This effect may be explained by interference with the repair of DN
A-DNA interstrand crosslinks induced by cisplatin. Our results suggest that
nickel(II) at non-cytotosic concentrations inhibits nucleotide excision re
pair and possibly crosslink repair by interference with distinct steps of t
he respective repair pathways.