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New Molecular Markers for Prostate Tumor Imaging: A Study on 2‐Methylene Substituted Fatty Acids as New AMACR Inhibitors
Author(s) -
Morgenroth Agnieszka,
Urusova Elizaveta A.,
Dinger Cornelia,
AlMomani Ehab,
Kull Thomas,
Glatting Gerhard,
Frauendorf Holm,
Jahn Olaf,
Mottaghy Felix M.,
Reske Sven N.,
Zlatopolskiy Boris D.
Publication year - 2011
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201003176
Subject(s) - lncap , du145 , chemistry , prostate , prostate cancer , cancer research , biochemistry , medicine , cancer
The development of prostate carcinoma is associated with alterations in fatty acid metabolism. α‐Methylacyl‐CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the ( S )/( R )‐isomers of a range of α‐methylacyl‐CoA thioesters. AMACR is involved in the β‐oxidation of the dietary branched‐chain fatty acids and bile acid intermediates. It is highly expressed in prostate (more than 95 %), colon (92 %), and breast cancers (44 %) but not in the respective normal or hyperplastic tissues. Thus, targeting of AMACR could be a new strategy for molecular imaging and therapy of prostate and some other cancers. Unlabeled 2‐methylenacyl‐CoA thioesters ( 12 a – c ) were designed as AMACR binding ligands. The thioesters were tested for their ability to inhibit the AMACR‐mediated epimerization of (25 R )‐THC‐CoA and were found to be strong AMACR inhibitors. Radioiodinated ( E )‐ 131 I‐13‐iodo‐2‐methylentridec‐12‐enoic acid ( 131 I‐ 7 c ) demonstrated preferential retention in AMACR‐positive prostate tumor cells (LNCaP, LNCaP C4‐2wt and DU145) compared with both AMACR‐knockout LNCaP C4‐2 AMACR‐siRNA and benign BPH1 prostate cell lines. A significant protein‐bound radioactive fraction with main bands at 47 (sum of molecular weights of AMACR plus 12 c ), 70, and 75 kDa was detected in LNCaP C4‐2 wt cells. In contrast, only negligible amounts of protein‐bound radioactivity were found in LNCaP C4‐2 AMACR‐siRNA cells.