title: Hedgehog Proteins Consume Steroidal CYP17A1 Antagonists: Potential Therapeutic Significance in Advanced Prostate Cancer.
abstract: Abiraterone, a potent inhibitor of the human enzyme CYP17A1 (cytochrome P450c17), provides a last line of defense against ectopic androgenesis in advanced prostate cancer. Herein we report an unprecedented off-target interaction between abiraterone and oncogenic hedgehog proteins. Our experiments indicate that abiraterone and its structural congener, galeterone, can replace cholesterol as a substrate in a specialized biosynthetic event of hedgehog proteins, known as cholesterolysis. The off-target reaction generates covalent hedgehog-drug conjugates. Cell-based reporter assays indicate that these conjugates activate hedgehog signaling when present in the low nanomolar range. Because hedgehog signaling is implicated in prostate cancer progression, and abiraterone is administered to treat advanced stages of the disease, this off-target interaction may have therapeutic significance.
authors.affiliation: Chemistry Department, State University of New York at Binghamton, 4400 Vestal Parkway East, Binghamton, NY, 13902, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Bordeau
authors.affiliation: Chemistry Department, State University of New York at Binghamton, 4400 Vestal Parkway East, Binghamton, NY, 13902, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Ciulla
authors.affiliation: Chemistry Department, State University of New York at Binghamton, 4400 Vestal Parkway East, Binghamton, NY, 13902, USA. callahan@binghamton.edu.
authors.forename: Brian P
authors.identifier: 0000-0003-4826-0162
authors.initials: BP
authors.lastname: Callahan
mesh_terms: D000736:Androstenes / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone
keywords: CYP17A1; androgens; cholesterol; hedgehog; prostate cancer