Carcinogenesis, Vol. 20, No. 7, 1177-1184,
July 1999
© 1999 Oxford University Press
Cancer Biology |
Nickel(II) increases the sensitivity of V79 Chinese hamster cells towards cisplatin and transplatin by interference with distinct steps of DNA repair
University of Karlsruhe, Department of Food Chemistry, Postfach 6980,D-76128 Karlsruhe, Germany and
1 MGC–Department of Radiation Genetics and Chemical Mutagenesis, Leiden University, Leiden, The Netherlands
Nickel compounds are carcinogenic to humans and to experimental animals. In contrast to their weak mutagenicity, they have been shown previously to increase UV-induced cytotoxicity and mutagenicity and to interfere with the repair of UV-induced DNA lesions by disrupting DNA–protein interactions involved in DNA damage recognition. In the present study we 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 µM and higher caused a pronounced increase in cisplatin-, transplatin- and mitomycin C-induced cytotoxicity, which was neither due to an altered uptake of cisplatin or transplatin nor to an increase in DNA adduct formation. However, nickel(II) inhibited the repair of cisplatin- and transplatin-induced DNA lesions. In combination with transplatin, it decreased the incision frequency, indicating that the DNA damage recognition/incision step during nucleotide excision repair is affected in general by nickel(II). In support of this, concentrations as low as 10 µM nickel(II) decreased binding of the xeroderma pigmentosum complementation group A protein to a cisplatin-damaged oligonucleotide. When combined with cisplatin, the incision frequency was affected only marginally, 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 DNA–DNA interstrand crosslinks induced by cisplatin. Our results suggest that nickel(II) at non-cytotoxic concentrations inhibits nucleotide excision repair and possibly crosslink repair by interference with distinct steps of the respective repair pathways.
Abbreviations: MEM
, -modified minimal essential medium; NER, nucleotide excision repair; XPA, xeroderma pigmentosum complementation group A.
2 To whom correspondence should be addressed. Email: andrea.hartwig{at}chemie.uni-karlsruhe.de
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