title: A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.
abstract: Although ∼50% of all types of human cancers harbour wild-type TP53, this p53 tumour suppressor is often deactivated through a concerted action by its abnormally elevated suppressors, MDM2, MDMX or SIRT1. Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress. Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro. Remarkably, INZ inhibits cell proliferation, induces senescence and tumour-specific apoptosis, and represses the growth of xenograft tumours derived from p53-harbouring H460 and HCT116 cells without causing apparent toxicity to normal tissues and the tumour-bearing SCID mice. Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.
authors.affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Shelya X
authors.initials: SX
authors.lastname: Zeng
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Derong
authors.initials: D
authors.lastname: Ding
authors.forename: Qizhuang
authors.initials: Q
authors.lastname: Ye
authors.forename: Samy O
authors.initials: SO
authors.lastname: Meroueh
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010640:Phenothiazines / Q000494:pharmacology / Q000627:therapeutic use*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010640:Phenothiazines; D016159:Tumor Suppressor Protein p53; C573921:inauzhin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C447939:SIRT1 protein, human; D056564:Sirtuin 1