title: Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators.
abstract: One of the best-studied temperature-gated channels is transient receptor potential melastatin 8 (TRPM8), which is activated by cold and cooling agents, such as menthol. Besides inducing a cooling sensation in sensory neurons, TRPM8 channel activation also plays a major role in physiopathology. Indeed, TRPMP8 expression increases in early stages of prostate cancer and its involvement in prostate cell apoptosis has recently been demonstrated. Thus, as TRPM8 is a tumor marker with significant potential use in diagnosis, as well as a target for cancer therapy, there is a need for new TRPM8-specific ligands. In this study, we investigated the action of "WS" compounds on TRPM8 channels. We compared the affinity of these molecules to that of menthol and icilin. This enabled us to identify new TRPM8 agonists. The menthol analog with the highest affinity, WS-12, had an EC(50) value about 2000 times lower than that of menthol and is, therefore, the highest-affinity TRPM8 ligand known to date. Finally, incorporating a fluorine atom in the WS-12 retained 75% of the activity of the parent compound. The high affinity of this new TRPM8 ligand and the possibility of incorporating a radiohalogen could thus be useful for diagnosis, monitoring and, perhaps, even therapy of prostate cancer.
authors.affiliation: Inserm, U800, Equipe Labellisée par la Ligue Contre le Cancer, Villeneuve d'Ascq F-59650, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beck
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bidaux
authors.forename: Alexis
authors.initials: A
authors.lastname: Bavencoffe
authors.forename: Loic
authors.initials: L
authors.lastname: Lemonnier
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thebault
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Shuba
authors.forename: Greg
authors.initials: G
authors.lastname: Barrit
authors.forename: Roman
authors.initials: R
authors.lastname: Skryma
authors.forename: Natalia
authors.initials: N
authors.lastname: Prevarskaya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000982:Antipruritics / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000819:agonists* / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008297:Male; D008610:Menthol / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000628:therapy; D011744:Pyrimidinones / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000819:agonists* / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D000982:Antipruritics; D014408:Biomarkers, Tumor; D008024:Ligands; D011744:Pyrimidinones; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D008610:Menthol; C490483:icilin