Synergy between cisplatin and an inhibitor of S-adenosylmethionine dependent transmethylation in human ovarian adenocarcinoma cells

Abstract

Selection of cells for resistance to cisplatin results in resistance to arsenite and selenite. Mammalian cells detoxify arsenite and selenite by S-adenosylmethionine dependent methylation. We aimed to investigate whether S-adenosylmethionine dependent methylation is involved in the cellular metabolism of cisplatin. Treatment of human ovarian cancer cells 2008 and the cisplatin-resistant subline 2008/C13*5.25 with the S-adenosylhomocysteine hydrolase inhibitor adenosine-dialdehyde, an indirect inhibitor of transmethylation, resulted in a significant elevation (16-fold in 2008, 6-fold in 2008/C13*5.25) in the cellular content of S-adenosylhomocysteine without changing S-adenosylmethionine. Adenosine dialdehyde synergistically enhanced the cytotoxicity of cisplatin and carboplatin as evidenced by combination indices <1 using the combination index-isobologram method in clonogenic assays with 2008 human ovarian adenocarcinoma cells. However, the cellular accumulation, efflux, steady state content, and the formation of DNA adducts of the cisplatin [H-3]-DEP were not affected by adenosine-dialdehyde. Sodium arsenite was significantly more toxic in mice pretreated with adenosine-dialdehyde, whereas the toxicity of cisplatin remained unchanged. These studies suggest that inhibition of S-adenosylmethionine dependent transmethylation enhanced the toxicity of cisplatin and carboplatin to human ovarian carcinoma cells in vitro without directly affecting the metabolism of either platinum drug.