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.
Hsieh
T C
TC
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla 10595, USA.
Wu
J M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D018809:Proliferating Cell Nuclear Antigen; D011944:Receptors, Androgen; D017313:Fenretinide; D017430:Prostate-Specific Antigen