Journal Article

Nickel(II) increases the sensitivity of V79 Chinese hamster cells towards cisplatin and transplatin by interference with distinct steps of DNA repair

Ines Krueger, Leon H.F. Mullenders and Andrea Hartwig

in Carcinogenesis

Volume 20, issue 7, pages 1177-1184
Published in print July 1999 | ISSN: 0143-3334
Published online July 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.7.1177
Nickel(II) increases the sensitivity of V79 Chinese hamster cells towards cisplatin and transplatin by interference with distinct steps of DNA repair

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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.

Keywords: MEMα, α-modified minimal essential medium; NER, nucleotide excision repair; XPA, xeroderma pigmentosum complementation group A.

Journal Article.  5893 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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