A new class of inhibitors of 2-arachidonoylglycerol hydrolysis and invasion of prostate cancer cells.
Endogenous 2-arachidonoylglycerol (2-AG) inhibits invasion of androgen-independent prostate cancer cells. Blocking cellular hydrolysis of 2-AG to increase its endogenous concentration results in a decrease in cell invasion. A series of compounds containing a trifluoromethyl ketone (TFK) moiety or the methyl analog (known to inhibit carboxylesterases) were investigated for their ability to inhibit 2-AG hydrolysis and prostate cancer cell invasion. Compounds containing a thioether beta to a TFK moiety inhibited 2-AG hydrolysis as well as cell invasion in a concentration-dependent manner. Inhibition of 2-AG hydrolysis increased concomitantly with inhibitor alkyl chain length from 4- to 12-carbons while inhibition of cell invasion exhibited a maximum at 8- to 10-carbons of the compounds. These results demonstrate a new series of 2-AG hydrolysis inhibitors as a potential therapeutic approach for prostate cancer.
Nithipatikom
Kasem
K
Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. kasemn@mcw.edu
Endsley
Michael P
MP
Isbell
Marilyn A
MA
Wheelock
Craig E
CE
Hammock
Bruce D
BD
Campbell
William B
WB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003094:Collagen / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005989:Glycerides / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007659:Ketones / Q000737:chemistry; D007797:Laminin / Q000737:chemistry; D008297:Male; D008956:Models, Chemical; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D011509:Proteoglycans / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013440:Sulfides / Q000737:chemistry
D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D004338:Drug Combinations; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D007659:Ketones; D007797:Laminin; D011509:Proteoglycans; D013440:Sulfides; C059485:matrigel; C094503:glyceryl 2-arachidonate; D003094:Collagen