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An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium

Authors
Journal
British Journal of Cancer
0007-0920
Publisher
Nature Publishing Group
Publication Date
Identifiers
DOI: 10.1038/sj.bjc.6602024
Keywords
  • Experimental Therapeutics
Disciplines
  • Medicine

Abstract

An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium RG Keedwell1, Y Zhao2, LA Hammond3, K Wen1, S Qin2, LI Atangan2, D-L Shurland2, DMA Wallace4, R Bird1, A Reitmair2, RAS Chandraratna2,5 and G Brown*,1 1Divisions of Immunity and Infection, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, UK; 2Department of Biology, Allergan Inc., Irvine, CA, USA; 3Divisions of Cancer Studies, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, UK; 4Department of Urology, Queen Elizabeth Hospital, Birmingham B15 2TH, USA; 5Retinoid Research, Department of Chemistry, Allergan Inc., Irvine, CA, USA 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 (atB250 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% atB1mM. The growth of tumour cells was also inhibited more than that of normal cells when RARb together with RARg, but not RARa 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 p21waf1. 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

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