title: Wild-type p53 reactivation by small-molecule Minnelide™ in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  The incidence of high-risk human papillomavirus (HR-HPV) head and neck squamous cell carcinoma (HNSCC) continues to increase, particularly oropharyngeal squamous cell carcinoma (OPSCC) cases. The inactivation of the p53 tumor suppressor gene promotes a chain of molecular events, including cell cycle progression and apoptosis resistance. Reactivation of wild-type p53 function is an intriguing therapeutic strategy. The aim of this study was to investigate whether a novel compound derived from diterpene triepoxide (Minnelide™) can reactivate wild-type p53 function in HPV-positive HNSCC.
  
  
  METHODS
  For all of our in vitro experiments, we used 2 HPV-positive HNSCC cell lines, University of Michigan squamous cell carcinoma (UM-SCC) 47 and 93-VU-147, and 2 HPV-positive human cervical cancer cell lines, SiHa and CaSki. Cells were treated with different concentrations of triptolide and analyzed for p53 activation. Mice bearing UM-SCC 47 subcutaneous xenografts and HPV-positive patient-derived tumor xenografts were treated with Minnelide and evaluated for tumor growth and p53 activation.
  
  
  RESULTS
  In HPV-positive HNSCC, Minnelide reactivated p53 by suppressing E6 oncoprotein. Activation of apoptosis followed, both in vitro and in vivo. In 2 preclinical HNSCC animal models (a subcutaneous xenograft model and a patient-derived tumor xenograft model), Minnelide reactivated p53 function and significantly decreased tumor progression and tumor volume.
  
  
  CONCLUSIONS
  Triptolide and Minnelide caused cell death in vitro and in vivo in HPV-positive HNSCC by reactivating wild-type p53 and thus inducing apoptosis. In addition, in 2 HPV-positive HNSCC animal models, Minnelide decreased tumor progression and induced apoptosis.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, United States. Electronic address: caic0001@umn.edu.
authors.forename: Emiro
authors.initials: E
authors.lastname: Caicedo-Granados
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, United States.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Fujisawa
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Minnesota, United States.
authors.forename: Bevan
authors.initials: B
authors.lastname: Yueh
authors.affiliation: Department of Surgery, University of Minnesota, United States.
authors.forename: Veena
authors.initials: V
authors.lastname: Sangwan
authors.affiliation: Department of Surgery, University of Minnesota, United States.
authors.forename: Ashok
authors.initials: A
authors.lastname: Saluja
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000378:metabolism; D006801:Humans; D051379:Mice; D010755:Organophosphates / Q000494:pharmacology*; D030361:Papillomavirus Infections / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D010755:Organophosphates; D010616:Phenanthrenes; D016159:Tumor Suppressor Protein p53; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt
keywords: HPV; Minnelide; Oropharyngeal cancer; Preclinical animal model; p53 Reactivation