Just when it seems that scientists are winning the fight against cancer, tumors hit below the belt by developing resistance to chemotherapies. But researchers at the University of Glasgow and TopoTarget Prolifix Ltd. have shown that delivering a 1-2 punch of epigenetic drugs could allow the chemotherapeutic agent cisplatin to knock out resistant tumors.
Cisplatin, a drug used to treat some forms of cancer, triggers tumor cell apoptosis by causing DNA crosslinking. Cancer cells can acquire cisplatin resistance by several mechanisms, including epigenetic inactivation of the MLH1 DNA mismatch repair gene. Previous studies have shown that the treatment of cisplatin-resistant cell lines with decitabine, a DNA methyltransferase inhibitor, induces the partial reversal of DNA methylation, re-expression of MLH1, and sensitivity to cisplatin. But the dose-limiting toxicity of decitabine, as well as the eventual re-methylation of genes in treated cells, has limited the clinical use of this epigenetic drug.
In the present study, the investigators showed that the combination of low doses of decitabine and belinostat, a histone deacetylase (HDAC) inhibitor, increased hMLH1 expression and cisplatin sensitivity in human ovarian tumor xenografts compared with decitabine alone.
Because HDAC inhibitors cannot induce the expression of genes silenced by promoter methylation, belinostat by itself had no effect on hMLH1 levels. In decitabine-treated cells, however, belinostat might improve access of transcription factors to the demethylated hMLH1 promoter by increasing histone acetylation and chromatin remodeling. Therefore, the combination of decitabine and belinostat could enhance the efficacy of chemotherapy for tumors that have acquired resistance due to gene silencing. Get in on all the action at British Journal of Cancer, March 2009.