title: A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer.
abstract: Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles' charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Monica
authors.initials: M
authors.lastname: Archibald
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Tara
authors.initials: T
authors.lastname: Pritchard
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Hayley
authors.initials: H
authors.lastname: Nehoff
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; Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain.
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Taurin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers; D016503:Drug Delivery Systems; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008297:Male; D008298:Maleates / Q000008:administration & dosage / Q000737:chemistry*; D008823:Micelles; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011137:Polystyrenes / Q000008:administration & dosage / Q000737:chemistry*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology*; D011743:Pyrimidines / Q000008:administration & dosage; D000077157:Sorafenib; D014407:Tumor Cells, Cultured
chemical_list: D004337:Drug Carriers; D008298:Maleates; D008823:Micelles; D010671:Phenylurea Compounds; D011137:Polystyrenes; D011743:Pyrimidines; C024074:styrene-maleic acid polymer; D009536:Niacinamide; D000077157:Sorafenib; C498826:nilotinib
keywords: castrate-resistant prostate cancer; nanomedicine; nilotinib; sorafenib; tyrosine kinase inhibitors
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