Abstract
The development of prostate carcinoma is associated with alterations in fatty acid metabolism. alpha-Methylacyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the (S)/(R)-isomers of a range of alpha-methylacyl-CoA thioesters. AMACR is involved in the beta-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.
Original language | English |
---|---|
Pages (from-to) | 10144-10150 |
Number of pages | 7 |
Journal | Chemistry: a European journal |
Volume | 17 |
Issue number | 36 |
DOIs | |
Publication status | Published - Aug 2011 |
Keywords
- antitumor agents
- fatty acids
- imaging agents
- inhibitors
- metabolism
- radiopharmaceuticals
- METHYLACYL-COA-RACEMASE
- C-11-CHOLINE PET/CT
- CANCER
- EXPRESSION
- ADENOCARCINOMA
- CARCINOMA
- DESIGN
- ENZYME
- ESTERS
- GENE