Aberrant epigenetic silencing of tumor suppressor genes has been recognized as a driving force in
cancer. Epigenetic drugs such as the DNA methylation inhibitor
decitabine reactivate genes and are effective in
myeloid leukemia, but resistance often develops and efficacy in solid
tumors is limited. To improve their clinical efficacy, we searched among approved anti-
cancer drugs for an epigenetic synergistic combination with
decitabine.
RESULTS: We used the YB5 cell line, a clonal derivative of the SW48
colon cancer cell line that contains a single copy of a hypermethylated cytomegalovirus (CMV) promoter driving
green fluorescent protein (GFP) to screen for drug-induced gene reactivation and synergy with
decitabine. None of the 16 anti-
cancer drugs tested had effects on their own. However, in combination with
decitabine,
platinum compounds showed striking synergy in activating GFP. This was dose dependent, observed both in concurrent and sequential combinations, and also seen with other
alkylating agents. Clinically achievable concentrations of
carboplatin at (25 μM) and
decitabine reactivated GFP in 28 % of the YB5 cells as compared to 15 % with
decitabine alone. Epigenetic synergy was also seen at endogenously hypermethylated tumor suppressor genes such as MLH1 and PDLIM4. Genome-wide studies showed that reactivation of hypermethylated genes by the combination was significantly better than that induced by
decitabine alone or
carboplatin alone.
Platinum compounds did not enhance
decitabine-induced hypomethylation. Rather, we found significantly inhibited HP1α expression by
carboplatin and the combination. This was accompanied by increased
histone H3 lysine 4 (H3K4) trimethylation and
histone H3 lysine 9 (H3K9) acetylation at reactivated genes (P < 0.0001) and reduced occupancy by methyl-
binding proteins including MeCP2 and methyl-CpG-binding domain
protein 2 (MBD2) (P < 0.0001).
CONCLUSIONS: