Wild-type p53 reactivation by small-molecule Minnelide™ in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma

Emiro Caicedo-Granados; Rui Lin; Caitlin Fujisawa; Bevan Yueh; Veena Sangwan; Ashok Saluja

doi:10.1016/j.oraloncology.2014.09.013

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Wild-type p53 reactivation by small-molecule Minnelide™ in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma

Journal article

Peer reviewed

Wild-type p53 reactivation by small-molecule Minnelide™ in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma

Emiro Caicedo-Granados, Rui Lin, Caitlin Fujisawa, Bevan Yueh, Veena Sangwan and Ashok Saluja

Oral oncology, Vol.50(12), pp.1149-1156

12/01/2014

DOI: 10.1016/j.oraloncology.2014.09.013

PMCID: PMC4678773

PMID: 25311433

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Abstract

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. 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. 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. 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.

Animals

Antineoplastic Agents, Alkylating - pharmacology

Apoptosis - drug effects

Carcinoma, Squamous Cell - drug therapy

Carcinoma, Squamous Cell - metabolism

Diterpenes - pharmacology

Epoxy Compounds - pharmacology

Head and Neck Neoplasms - drug therapy

Head and Neck Neoplasms - metabolism

Human papillomavirus 16 - metabolism

Humans

Mice

Organophosphates - pharmacology

Papillomavirus Infections - metabolism

Phenanthrenes - pharmacology

Treatment Outcome

Tumor Suppressor Protein p53 - drug effects

Tumor Suppressor Protein p53 - metabolism

Details

Title: Subtitle: Wild-type p53 reactivation by small-molecule Minnelide™ in human papillomavirus (HPV)-positive head and neck squamous cell carcinoma
Creators: Emiro Caicedo-Granados - University of Minnesota
Rui Lin - University of Minnesota
Caitlin Fujisawa - University of Minnesota
Bevan Yueh - University of Minnesota
Veena Sangwan - University of Minnesota
Ashok Saluja - University of Minnesota
Resource Type: Journal article
Publication Details: Oral oncology, Vol.50(12), pp.1149-1156
DOI: 10.1016/j.oraloncology.2014.09.013
PMID: 25311433
PMCID: PMC4678773
NLM abbreviation: Oral Oncol
ISSN: 1368-8375
eISSN: 1879-0593
Grant note: P30 CA077598 / NCI NIH HHS R01 CA124723 / NCI NIH HHS
Language: English
Date published: 12/01/2014
Academic Unit: Otolaryngology
Record Identifier: 9984966848502771

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