Effects of fenretinide (4-HPR) on prostate LNCaP cell growth, apoptosis, and prostate-specific gene expression

BACKGROUND: Although fenretinide (4-HPR) is currently being evaluated in a phase II clinical study for the chemoprevention of prostate cancer [Greenwald et al.: CA 45:31-49, 1995], the mechanism underlying its antineoplastic activity has not been elucidated. METHODS: Androgen-dependent human prostatic LNCaP cells cultured with fetal bovine serum (FBS) were treated with 4-HPR and evaluated for effects on cell growth and cell cycle phase distribution, induction of apoptosis, and changes in proliferating cell nuclear antigen (PCNA), prostate-specific antigen (PSA), and androgen receptor (AR) levels. RESULTS: LNCaP cells treated with 4-HPR for 6 days showed 82-95% suppression of cell growth, with accompanying time- and dose-dependent downregulation of PCNA, a partial arrest in G1 phase of the cell cycle, and a marked increase in the percentage of apoptotic cells. Apoptosis was demonstrated by the characteristic DNA fragmentation pattern seen on agarose gels, and by flow cytometric analysis. 4-HPR-induced prostate-specific phenotype changes included significant downregulated expression of both intracellular and secreted forms of PSA, which were preceded by a reduction of AR expression. CONCLUSIONS: These data suggest that 4-HPR acts as a pleiotropic effector of prostate cell growth and specific gene expression.