title: A novel role for raloxifene nanomicelles in management of castrate resistant prostate cancer.
abstract: Of patients with castrate resistant prostate cancer (CRPC), less than 25-33% survive more than five years. Recent studies have implicated estrogen, acting either alone or synergistically with androgens in the development of castrate resistant prostate cancer. Several in vitro and in vivo studies, as well as a limited number of clinical trials, have highlighted the potential of selective estrogen receptor modulators, such as raloxifene (Ral) for the treatment of castrate resistant prostate cancer. However, the poor oral bioavailability and metabolism of selective estrogen receptor modulators limit their efficiency in clinical application. To overcome these limitations, we have used styrene co-maleic acid (SMA) micelle to encapsulate raloxifene. Compared to free drug, SMA-Ral micelles had 132 and 140% higher cytotoxicity against PC3 and DU 145 prostate cell lines, respectively. SMA-Ral effectively inhibits cell cycle progression, increases apoptosis, and alters the integrity of tumor spheroid models. In addition, the micellar system induced changes in expression and localization of estrogen receptors, epidermal growth factor receptor (EGFR), and downstream effectors associated with cell proliferation and survival. Finally, SMA-Ral treatment decreased migration and invasion of castrate resistant prostate cancer cell lines. In conclusion, SMA-Ral micelles can potentially benefit new strategies for clinical management of castrate resistant prostate cancer.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Sebastien
authors.identifier: 0000-0003-2167-5253
authors.initials: S
authors.lastname: Taurin
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Hayley
authors.identifier: 0000-0001-5790-8245
authors.initials: H
authors.lastname: Nehoff
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Thalita
authors.identifier: 0000-0002-1641-6719
authors.initials: T
authors.lastname: van Aswegen
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Rhonda J
authors.initials: RJ
authors.lastname: Rosengren
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand ; Department of Oncology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008297:Male; D008298:Maleates / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D009336:Necrosis; D009361:Neoplasm Invasiveness; D011137:Polystyrenes / Q000737:chemistry; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D020849:Raloxifene Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D008298:Maleates; D008823:Micelles; D011137:Polystyrenes; D011960:Receptors, Estrogen; C024074:styrene-maleic acid polymer; D020849:Raloxifene Hydrochloride; D020780:Matrix Metalloproteinase 9