title: Selective activity of deguelin identifies therapeutic targets for androgen receptor-positive breast cancer.
abstract: Triple-negative breast cancers (TNBC) are aggressive malignancies with no effective targeted therapies. Recent gene expression profiling of these heterogeneous cancers and the classification of cell line models now allows for the identification of compounds with selective activities against molecular subtypes of TNBC. The natural product deguelin was found to have selective activity against MDA-MB-453 and SUM-185PE cell lines, which both model the luminal androgen receptor (LAR) subtype of TNBC. Deguelin potently inhibited proliferation of these cells with GI50 values of 30 and 61 nM, in MDA-MB-453 and SUM-185PE cells, respectively. Deguelin had exceptionally high selectivity, 197 to 566-fold, for these cell lines compared to cell lines representing other TNBC subtypes. Deguelin's mechanisms of action were investigated to determine how it produced these potent and selective effects. Our results show that deguelin has dual activities, inhibiting PI3K/Akt/mTOR signaling, and decreasing androgen receptor levels and nuclear localization. Based on these data, we hypothesized that the combination of the mTOR inhibitor rapamycin and the antiandrogen enzalutamide would have efficacy in LAR models. Rapamycin and enzalutamide showed additive effects in MDA-MB-453 cells, and both drugs had potent antitumor efficacy in a LAR xenograft model. These results suggest that the combination of antiandrogens and mTOR inhibitors might be an effective strategy for the treatment of androgen receptor-expressing TNBC.
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Robles
authors.affiliation: Natural Product Discovery Group, Institute for Natural Products Applications and Research Technologies, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA.|Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA.
authors.forename: Shengxin
authors.initials: S
authors.lastname: Cai
authors.affiliation: Natural Product Discovery Group, Institute for Natural Products Applications and Research Technologies, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA. Rhcichewicz@ou.edu.|Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, 101 Stephenson Parkway, Norman, OK, 73019, USA. Rhcichewicz@ou.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cichewicz
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. Mooberry@uthscsa.edu.|Cancer Therapy & Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. Mooberry@uthscsa.edu.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001549:Benzamides; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; D012402:Rotenone; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C410798:AR protein, human; C540278:enzalutamide; C546842:MTOR protein, human; C107676:deguelin
keywords: Deguelin; Enzalutamide; Luminal androgen receptor; Natural products; Triple-negative breast cancer; mTOR