title: Identification of aneuploidy-selective antiproliferation compounds.
abstract: Aneuploidy, an incorrect chromosome number, is a hallmark of cancer. Compounds that cause lethality in aneuploid, but not euploid, cells could therefore provide new cancer therapies. We have identified the energy stress-inducing agent AICAR, the protein folding inhibitor 17-AAG, and the autophagy inhibitor chloroquine as exhibiting this property. AICAR induces p53-mediated apoptosis in primary mouse embryonic fibroblasts (MEFs) trisomic for chromosome 1, 13, 16, or 19. AICAR and 17-AAG, especially when combined, also show efficacy against aneuploid human cancer cell lines. Our results suggest that compounds that interfere with pathways that are essential for the survival of aneuploid cells could serve as a new treatment strategy against a broad spectrum of human tumors.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
authors.forename: Yun-Chi
authors.initials: YC
authors.lastname: Tang
authors.forename: Bret R
authors.initials: BR
authors.lastname: Williams
authors.forename: Jake J
authors.initials: JJ
authors.lastname: Siegel
authors.forename: Angelika
authors.initials: A
authors.lastname: Amon
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000494:pharmacology; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D020090:Chromosome Segregation; D004354:Drug Screening Assays, Antitumor; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D012265:Ribonucleotides / Q000494:pharmacology; D014314:Trisomy
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C112765:tanespimycin; D002738:Chloroquine; C031143:AICA ribonucleotide