title: Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane.
abstract: Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSE) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared with vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC. Cancer Prev Res; 9(7); 547-57. ©2016 AACR.
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Malabika
authors.initials: M
authors.lastname: Sen
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Changyou
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Egner
authors.affiliation: Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Jed W
authors.initials: JW
authors.lastname: Fahey
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Normolle
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, San Francisco, California.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland. Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. johnsond@pitt.edu.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001937:Brassica; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D018592:Cross-Over Studies; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009062:Mouth Neoplasms / Q000517:prevention & control*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects; D010865:Pilot Projects; D010936:Plant Extracts / Q000494:pharmacology*; D013454:Sulfoxides
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010936:Plant Extracts; D013454:Sulfoxides; C016766:sulforaphane