An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium.
Screening of synthetic retinoids for activity against prostate carcinoma cell lines has identified antagonists of retinoic acid receptors (RARs) as potent growth inhibitors (Hammond et al, 2001, Br J Cancer 85, 453-462). Here we report that 5 days of exposure to a high-affinity pan-RAR antagonist (AGN194310) abolished growth of prostate carcinoma cells from 14 out of 14 patients, with half-maximal inhibition between 200 and 800 nM. It had similar effects (at approximately 250 nM) on the prostate carcinoma lines LNCaP, DU-145 and PC-3. AGN194310 inhibited the growth of normal prostate epithelium cells less potently, by 50% at approximately 1 microM. The growth of tumour cells was also inhibited more than that of normal cells when RARbeta together with RARgamma, but not RARalpha alone, were antagonised. Treatment of LNCaP cells with AGN194310 arrested them in G1 of cell cycle within 12 h, with an accompanying rise in the level of p21(waf1). The cells underwent apoptosis within 3 days, as indicated by mitochondrial depolarisation, Annexin V binding and DNA fragmentation. Apoptosis was caspase-independent: caspases were neither cleaved nor activated, and DNA fragmentation was unaffected by the pan-caspase inhibitor Z-VAD-FMK. The ability of AGN 194310 to induce apoptosis of prostate cancer cells and its differential effect on malignant and normal prostate epithelial cells suggests that this compound may be useful in the treatment of prostate cancer.
Keedwell
R G
RG
Divisions of Immunity and Infection, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, UK.
Zhao
Y
Y
Hammond
L A
LA
Wen
K
K
Qin
S
S
Atangan
L I
LI
Shurland
D-L
DL
Wallace
D M A
DM
Bird
R
R
Reitmair
A
A
Chandraratna
R A S
RA
Brown
G
G
D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology*; D020169:Caspases / Q000494:pharmacology; D004249:DNA Damage; D004847:Epithelial Cells; D006801:Humans; D008297:Male; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000473:pathology*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C121616:4-((4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl)ethynyl)benzoic acid; D001565:Benzoates; D018168:Receptors, Retinoic Acid; D013876:Thiophenes; D020169:Caspases