Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane

被引:81
作者
Bauman, Julie E. [1 ,2 ]
Zang, Yan [1 ]
Sen, Malabika [3 ]
Li, Changyou [1 ]
Wang, Lin [3 ]
Egner, Patricia A. [4 ]
Fahey, Jed W. [5 ,6 ]
Normolle, Daniel P. [2 ,7 ]
Grandis, Jennifer R. [8 ]
Kensler, Thomas W. [2 ,4 ,6 ,9 ]
Johnson, Daniel E. [1 ,3 ,9 ]
机构
[1] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA
[3] Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA USA
[4] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA
[5] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA
[6] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD USA
[7] Univ Pittsburgh, Sch Med, Dept Biostat, Pittsburgh, PA USA
[8] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, San Francisco, CA 94143 USA
[9] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA
关键词
SQUAMOUS-CELL CARCINOMA; BROCCOLI SPROUT BEVERAGES; RANDOMIZED CLINICAL-TRIAL; 2ND PRIMARY TUMORS; NECK-CANCER; AIRBORNE POLLUTANTS; DOUBLE-BLIND; PHASE-II; HEAD; CHEMOPREVENTION;
D O I
10.1158/1940-6207.CAPR-15-0290
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2016 AACR.
引用
收藏
页码:547 / 557
页数:11
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