Effects of interleukin-1 alpha on DNA repair in human ovarian carcinoma (NIH:OVCAR-3) cells: implications in the mechanism of sensitization of cis-diamminedichloroplatinum(II).
The cytokine interleukin-1 alpha (IL-1 alpha) showed a cytostatic effect on human ovarian carcinoma cells and significantly enhanced the antiproliferative activity of cis-diamminedichloroplatinum(II) (cisplatin) toward the NIH:OVCAR-3 tumor cell line in culture. The factor of sensitization was 15-20-fold. The maximum levels of sensitization were observed both with simultaneous exposure to cisplatin and IL-1 alpha and with 24-hr pretreatment with IL-1 alpha. Synergy between these agents was diminished when cells were pretreated with an IL-1 alpha-specific receptor antagonist, indicating that synergistic interaction was receptor mediated. Using atomic absorption spectroscopy, we evaluated the cellular accumulation of cisplatin and the DNA platination; the results showed that IL-1 alpha increased cellular accumulation of cisplatin and DNA platination. Cisplatin did not affect IL-1 alpha accumulation in NIH:OVCAR-3 cells. Further studies showed that IL-1 alpha reduced the removal of platinum from DNA. These results strongly suggest that IL-1 alpha inhibits DNA repair, and this decrease in DNA repair may explain, in part, the strong synergistic interaction between IL-1 alpha and cisplatin in NIH:OVCAR-3 cells.
Benchekroun
M N
MN
Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Parker
R
R
Dabholkar
M
M
Reed
E
E
Sinha
B K
BK
D002945:Cisplatin / Q000494:pharmacology*; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D012795:Sialoglycoproteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018736:DNA Adducts; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; C057270:cisplatin-DNA adduct; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin