title: Epigenetic synergy between decitabine and platinum derivatives.
abstract: BACKGROUND
  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
  Our results suggest that the combination of decitabine with platinum analogs shows epigenetic synergy that might be exploited in the treatment of different cancers.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Taichun
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Jiali
authors.initials: J
authors.lastname: Si
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.|Fels Institute for Cancer Research and Molecular Biology, Temple University, 3307 North Broad Street, Rm 154, PAHB, Philadelphia, PA 19140 USA.
authors.forename: Noël J-M
authors.initials: NJ
authors.lastname: Raynal
authors.affiliation: Harbin Institute of Hematology & Oncology, Harbin, 150010 China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Vazganush
authors.initials: V
authors.lastname: Gharibyan
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Saira
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.|Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Shu
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.|Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.
authors.forename: Marcos Rh
authors.initials: MR
authors.lastname: Estecio
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.|Fels Institute for Cancer Research and Molecular Biology, Temple University, 3307 North Broad Street, Rm 154, PAHB, Philadelphia, PA 19140 USA.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.|Fels Institute for Cancer Research and Molecular Biology, Temple University, 3307 North Broad Street, Rm 154, PAHB, Philadelphia, PA 19140 USA.
authors.forename: Jean-Pierre J
authors.initials: JJ
authors.lastname: Issa
keywords: 5-aza-2′-deoxycytidine; Carboplatin; DNA methylation; Epigenetic reactivation; Tumor suppressor genes