New molecular markers for prostate tumor imaging: a study on 2-methylene substituted fatty acids as new AMACR inhibitors.

Abstract

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 (25R)-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.

• Authors: Agnieszka Morgenroth, Elizaveta A Urusova, Cornelia Dinger, Ehab Al-Momani, Thomas Kull, Gerhard Glatting, Holm Frauendorf, Olaf Jahn, Felix M Mottaghy, Sven N Reske, Boris D Zlatopolskiy
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 17 Issue 36 Pg. 10144-50 (Aug 29 2011) ISSN: 1521-3765 [Electronic] Germany
• PMID: 21812041 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Enzyme Inhibitors
• Fatty Acids
• Racemases and Epimerases
• alpha-methylacyl-CoA racemase

Topics

• Carcinoma (diagnosis, enzymology)
• Cell Line, Tumor
• Cell Tracking (methods)
• Enzyme Inhibitors (chemical synthesis, chemistry)
• Fatty Acids (chemical synthesis, chemistry)
• Humans
• Male
• Prostatic Neoplasms (diagnosis, enzymology)
• Racemases and Epimerases (antagonists & inhibitors)