title: Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents.
abstract: Manipulation of the activity of the p53 tumor suppressor pathway has demonstrated potential benefit in preclinical mouse tumor models and has entered human clinical trials. We describe here an improved, extensive small-molecule chemical compound library screen for p53 pathway activation in a human cancer cell line devised to identify hits with potent antitumor activity. We uncover six novel small-molecule lead compounds, which activate p53 and repress the growth of human cancer cells. Two tested compounds suppress in vivo tumor growth in an orthotopic mouse model of human B-cell lymphoma. All compounds interact with DNA, and two activate p53 pathway in a DNA damage signaling-dependent manner. A further screen of a drug library of approved drugs for medicinal uses and analysis of gene-expression signatures of the novel compounds revealed similarities to known DNA intercalating and topoisomerase interfering agents and unexpected connectivities to known drugs without previously demonstrated anticancer activities. These included several neuroleptics, glycosides, antihistamines and adrenoreceptor antagonists. This unbiased screen pinpoints interference with the DNA topology as the predominant mean of pharmacological activation of the p53 pathway and identifies potential novel antitumor agents.
authors.affiliation: Molecular Cancer Biology Program and Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Karita
authors.initials: K
authors.lastname: Peltonen
authors.forename: Laureen
authors.initials: L
authors.lastname: Colis
authors.forename: Hester
authors.initials: H
authors.lastname: Liu
authors.forename: Sari
authors.initials: S
authors.lastname: Jäämaa
authors.forename: Henna M
authors.initials: HM
authors.lastname: Moore
authors.forename: Juulia
authors.initials: J
authors.lastname: Enbäck
authors.forename: Pirjo
authors.initials: P
authors.lastname: Laakkonen
authors.forename: Anne
authors.initials: A
authors.lastname: Vaahtokari
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Taija M
authors.initials: TM
authors.lastname: af Hällström
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53