title: Epigenetic targeting of ovarian cancer stem cells.
abstract: Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.
authors.forename: Yinu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cardenas
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Condello
authors.affiliation: Astex Pharmaceuticals, Inc., Dublin, California.
authors.forename: Pietro
authors.initials: P
authors.lastname: Taverna
authors.affiliation: Center for Computational Biology and Bioinformatics, Indianapolis, Indiana.
authors.forename: Matthew
authors.initials: M
authors.lastname: Segar
authors.affiliation: Center for Computational Biology and Bioinformatics, Indianapolis, Indiana. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: knephew@indiana.edu dmatei@iupui.edu.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana. VA Roudebush Hospital, Indianapolis, Indiana. knephew@indiana.edu dmatei@iupui.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: C580831:guadecitabine; D016190:Carboplatin; D000444:Aldehyde Dehydrogenase; D001374:Azacitidine