S-adenosyl methionine specifically protects the anticancer effect of 5-FU via DNMTs expression in human A549 lung cancer cells

Abstract

Abstract. Cellular methylation is associated with stabilization of the chromatin structure. S-adenosyl methionine (SAM), a metabolite of methionine metabolism, is the methyl donor of essential cellular methyltransferase reactions. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyl tetrazolium bromide (MTT) assay, we found that combination treatment of SAM and 5-fluorouracil (5-FU) specifically protected the anticancer effect of 5-FU, whereas the combination of SAM and cisplatin had no effect. This result was confirmed by FACS analysis. The combination treatment of SAM and 5-FU significantly decreased the dead cell population, while the G1 cell population was slightly increased, suggesting that protection of SAM is not associated with the cell cycle arrest of DNA-damaging drugs. We also analyzed which cellular methylation-related proteins were involved in the protective effect. Results showed the expression of DNA methyltransferases (DNMTs) was decreased with 5-FU alone but was increased with the combination treatment of SAM and 5-FU, suggesting that SAM protects the anticancer effect of 5-FU by regulating the expression of DNMTs. Taken together, the results indicated that SAM specifically modulates the anticancer effect of the DNA damage agent 5-FU and this may be modulated by aberrant DNA methylation.

The effect of 5-fluorouracil/leucovorin chemotherapy on CpG methylation, or the confounding role of leukocyte heterogeneity: An illustration

“…In an in vitro DNA-based hybridization chain reaction assay, 5-FU inhibited the activity of DNA methyltransferase 23 . In human lung cancer cells, expression of DNA methyltransferases was decreased with 5-FU treatment alone, but increased when combined with S-adenosyl methionine, a methyl donor of essential methyltransferase reactions, indicating that the 5-FU may modulate aberrant DNA methylation 24 . In a human lung cancer cell line, higher concentrations of 5-FU induced significant DNA hypermethylation 25 .…”

DNA demethylation and invasive cancer: implications for therapeutics

“…Several studies demonstrated that SAM treatment had a chemopreventive effect in liver cancer in rat (Pascale et al, 2002). A possible mechanism for SAM action is silencing the expression of prometastatic genes through DNA methylation (van der Westhuyzen, 1985;Fuso et al, 2001;Ross, 2003;Pakneshan et al, 2004;Shukeir et al, 2006;Chik et al, 2014).Using several cytotoxic assays, it was demonstrated that SAM specifically enhances the anticancer effect of 5-FU, but not that of cisplatin (Ham et al, 2013). We have recently demonstrated that SAM antagonizes the effects of 5-azadC on cell invasiveness and increases the antigrowth effects of 5-azadC, more than this, SAM inhibited the global hypomethylation induced by 5-azadC (Figure 1) (Chik et al, 2014).…”

Study of the radiotherapy sensitization effects and mechanism of capecitabine (Xeloda) against non-small-cell lung cancer cell line A549

“…5-FU is the first radiotherapy sensitizer used in clinical practice; its mechanism is thought to be inhibition of DNA synthesis by inhibition of thymidylate synthase (Tano et al, 2013). Others have reported that 5-FU could significantly inhibit the proliferation of A549 cells and prolong the cell cycle (Ham et al, 2013), and induce the apoptosis of PANC-1 cells . Capecitabine has been widely used in the radiotherapy of gastrointestinal cancer and breast cancer as an oral 5-FU pro-drug (Zhou et al, 2013;Saif 2014;Wang et al, 2014).…”