인체대장암 세포에서 후성적 유전자 불활성화 저해제와 5-Fluorouracil의 병용효과분석

Combinatorial Effect of 5-FU and Epigenetic Silencing Repressors in Human Colorectal Cancer Cells

Low sensitivity to anticancer drugs such as 5-fluorouracil (5-FU) has been associated with decreased expression of genes involved in cell proliferation, apoptosis and metastasis. Recently, it has been shown that the expression levels of some of these genes are reduced by transcription inhibition due to epigenetic silencing on CpG islands. Therefore, epigenetic therapy has been proposed, where epigenetic silencing is repressed with DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors alone or in combination with other chemotherapeutic agents. The aim of our study was to evaluate the combination effect of 5-FU and its association with the status of epigenetic silencing using methylation-specific PCR of p14ARF when given with 5-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor and depsipeptide, and HDAC inhibitor in DLD-1 human colorectal cancer cells. The combination of 5-aza-dC with depsipeptide showed a synergism and induced unmethylation of p14ARF. However, triplet combination of 5-aza-dC/epsipeptide and 5-FU resulted in antagonistic effects and abrogated unmethylation of p14ARF. These results suggest that unfavorable interaction of 5-aza-dC/depsipeptide with 5-FU in DLD-1 cells may be related with the failure in repression of epigenetic silencing, which warrants further investigation.