title: Identification of a novel polyprenylated acylphloroglucinol‑derived SIRT1 inhibitor with cancer‑specific anti-proliferative and invasion-suppressing activities.
abstract: SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC(50) for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.
authors.affiliation: Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Lijia
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Boston, MA 02215, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Qi
authors.affiliation: Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Christine Ya-Chi
authors.initials: CY
authors.lastname: Chiao
authors.affiliation: Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Boston, MA 02215, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Boston, MA 02215, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.affiliation: Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.affiliation: Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010696:Phloroglucinol / Q000008:administration & dosage* / Q000031:analogs & derivatives; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D010696:Phloroglucinol; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2