FENRETINIDE-INDUCED APOPTOSIS OF HUMAN HEAD AND NECK SQUAMOUS CARCINOMA CELL-LINES

BACKGROUND: Squamous cell carcinoma of the head and neck (HNSCC) has a high incidence of recurrence and associated second primary malignancy . The retinoid 13-cis-retinoic acid has been shown to be effective as both a chemopreventive and chemotherapeutic agent for HNSCC, but often with treatment-limiting toxicity. The synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide) (HPR) has significant antiproliferativ e activity against a number of animal and human malignancies and has b een used in clinical trials as a chemopreventive agent in patients wit h breast and prostate cancer and oral leukoplakia. HPR has been shown to have a toxicity profile lower than that for other retinoids used in clinical trials. PURPOSE: The aim of this study was to investigate th e effect of HPR on the growth of HNSCC cell lines in vitro. METHODS: F our HNSCC cell lines (JHU-O11-SCC, JHU-020-SCC, JHU-022-SCC, and FaDu) were treated with a range of concentrations of HPR for various times. After HPR exposure, cell viability was determined by tetrazolium dye (MTT) colorimetric assay, comparing cell survival with that of untreat ed control cells, HPR-induced apoptosis was determined by flowcytometr ic deoxyribonucleic acid cell-cycle analysis, ultrastructural analysis with electron microscopy, and deoxyribonucleic acid fragmentation det ected by gel electrophoresis. RESULTS: HPR caused significant growth i nhibition in three of the four HNSCC cell lines in a dose-and time-dep endent fashion. In two cell lines (JHU-011-SCC, JHU-020-SCC) a signifi cant antiproliferative effect was achieved between 1 and 2.5 mu mol/L HPR after 72 hours of treatment. By deoxyribonucleic acid cell-cycle a nalysis, electron microscopy, and gel electrophoresis, HPR was shown t o induce apoptosis in the JHU-011-SCC and JHU-020-SCC cell lines, but not in the FaDu cell line, which was insensitive to the growth inhibit ory effect of HPR. CONCLUSIONS: This study has demonstrated that HPR r educes cell viability in HNSCC cells in vitro at clinically relevant d oses, with the growth inhibition occurring through the induction of ap optosis.