Guggulsterone and chemoprevention of head and neck squamous cell carcinoma.

PR-02

The invasiveness and high incidence of second primary tumors (SPTs) in head and neck squamous cell carcinoma (HNSCC) account for much of the morbidity and mortality associated with this carcinogen-induced neoplasm. Chemoprevention, aimed at counteracting the effects of carcinogens and/or preventing HNSCC SPTs and recurrence represents an important clinical goal. The aim of this study was to identify and characterize a naturally-occurring, plant-derived compound that has the potential for clinical use as a preventive therapy for HNSCC. Guggulsterone is a compound present in the extract of the Commiphora mukul plant, a component of traditional Indian medicine used to treat various illnesses. It has been shown to have in vitro anticancer activity in acute myeloid leukemia, prostate and lung cancers and, additionally, to suppress the activity of nuclear factor kappa B (NFκB), a transcription factor that promotes tumorigenesis in various cancers including HNSCC. We found that guggulsterone inhibits proliferation of 1483 and UM-22b HNSCC cell lines in a dose-dependent manner with IC50s of 2.5-5 µM, as determined by trypan blue dye exclusion assay. Furthermore, guggulsterone treatment (20 µM for 48 hours) resulted in an approximate two fold increase in cytoplasmic histone associated DNA fragmentation (apoptosis) in UM-22b cells. Treatment of 1483 and 22b cell lines for 24 hours increased the cell population in the G1 phase of the cell cycle at 10 µM by 13.2 and 6.6 % of the total population and at 20 µM by 30.4 and 15.6 % of the total population, respectively, as shown through propidium iodide staining and flow cytometric analysis. Signal transducer and activator of transcription (STAT)-3 is an oncogenic transcription factor known to be constitutively active in HNSCC and to promote cell survival and inhibit apoptosis in HNSCC cell lines and tumor xenografts. Guggulsterone-treated 1483 and UM-22b cells exhibited dose-dependent decreases in levels of both phosphotyrosine STAT3 (thought to be the active form) and total STAT3. Future in vivo studies evaluating guggulsterone's ability to prevent HNSCC will hopefully complement these in vitro studies in providing a basis for clinical trial of guggulsterone as a chemopreventive therapy for HNSCC.