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 antiproliferative activity against a number of animal and human malignancies and has been used in clinical trials as a chemopreventive agent in patients with 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.


OBJECTIVE
The aim of this study was to investigate the effect of HPR on the growth of HNSCC cell lines in vitro.


METHODS
Four HNSCC cell lines (JHU-011-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 untreated control cells. HPR-induced apoptosis was determined by flow-cytometric deoxyribonucleic acid cell-cycle analysis, ultrastructural analysis with electron microscopy, and deoxyribonucleic acid fragmentation detected by gel electrophoresis.


RESULTS
HPR caused significant growth inhibition in three of the four HNSCC cell lines in a dose- and time-dependent fashion. In two cell lines (JHU-011-SCC, JHU-020-SCC) a significant antiproliferative effect was achieved between 1 and 2.5 micromol/L HPR after 72 hours of treatment. By deoxyribonucleic acid cell-cycle analysis, electron microscopy, and gel electrophoresis, HPR was shown to 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 inhibitory effect of HPR.


CONCLUSIONS
This study has demonstrated that HPR reduces cell viability in HNSCC cells in vitro at clinically relevant doses, with the growth inhibition occurring through the induction of apoptosis.
Scher
R L
RL
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Saito
W
W
Dodge
R K
RK
Richtsmeier
W J
WJ
Fine
R L
RL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D017313:Fenretinide / Q000494:pharmacology*; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007822:Laryngeal Neoplasms / Q000473:pathology; D008854:Microscopy, Electron; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
D000970:Antineoplastic Agents; D017313:Fenretinide