title: The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer.
abstract: OBJECTIVE
  To investigate SGI-110 as a "chemosensitizer" in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer.
  
  
  METHODS
  Several ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR.
  
  
  RESULTS
  We demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant ovarian cancer cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes, and putative drivers of ovarian cancer cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced antitumor effects in ovarian cancer xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene-specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of ovarian cancer cisplatin resistance (MLH1 and ZIC1), differentiation-associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in ovarian cancer cells was increased by SGI-110, as measured by inductively coupled plasma-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage.
  
  
  CONCLUSIONS
  These results strongly support further investigation of hypomethylating strategies in platinum-resistant ovarian cancer. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting.
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Astex Pharmaceuticals Inc., Dublin, California.
authors.forename: Joanne
authors.initials: J
authors.lastname: Munck
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tang
authors.affiliation: Astex Pharmaceuticals Inc., Dublin, California.
authors.forename: Pietro
authors.initials: P
authors.lastname: Taverna
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.
authors.forename: Yinu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.
authors.forename: David F B
authors.initials: DF
authors.lastname: Miller
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana.
authors.forename: Jay
authors.initials: J
authors.lastname: Pilrose
authors.affiliation: Astex Pharmaceuticals Inc., Dublin, California.
authors.forename: Gavin
authors.initials: G
authors.lastname: Choy
authors.affiliation: Astex Pharmaceuticals Inc., Dublin, California.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Azab
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pawelczak
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Pamela
authors.initials: P
authors.lastname: VanderVere-Carozza
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Astex Pharmaceuticals Inc., Dublin, California.
authors.forename: John
authors.initials: J
authors.lastname: Lyons
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. VA Roudebush Hospital, Indianapolis, Indiana. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. knephew@indiana.edu jturchi@iupui.edu dmatei@iupui.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana. knephew@indiana.edu jturchi@iupui.edu dmatei@iupui.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Turchi
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana. knephew@indiana.edu jturchi@iupui.edu dmatei@iupui.edu.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D018736:DNA Adducts; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D006657:Histones; C580831:guadecitabine; D001374:Azacitidine; D002945:Cisplatin