title: The novel agent phospho-glycerol-ibuprofen-amide (MDC-330) inhibits glioblastoma growth in mice: an effect mediated by cyclin D1.
abstract: Given that glioblastoma multiforme (GBM) is associated with poor prognosis, new agents are urgently needed. We developed phospho-glycerol-ibuprofen-amide (PGIA), a novel ibuprofen derivative, and evaluated its safety and efficacy in preclinical models of GBM, and its mechanism of action using human GBM cells and animal tumor models. Furthermore, we explored whether formulating PGIA in polymeric nanoparticles could enhance its levels in the brain. PGIA was 3.7- to 5.1-fold more potent than ibuprofen in suppressing the growth of human GBM cell lines. PGIA 0.75× IC50 inhibited cell proliferation by 91 and 87% in human LN-229 and U87-MG GBM cells, respectively, and induced strong G1/S arrest.In vivo, compared with control, PGIA reduced U118-MG and U87-MG xenograft growth by 77 and 56%, respectively (P< 0.05), and was >2-fold more efficacious than ibuprofen. Normal human astrocytes were resistant to PGIA, indicating selectivity. Mechanistically, PGIA reduced cyclin D1 levels in a time- and concentration-dependent manner in GBM cells and in xenografts. PGIA induced cyclin D1 degradation via the proteasome pathway and induced dephosphorylation of GSK3β, which was required for cyclin D1 turnover. Furthermore, cyclin D1 overexpression rescued GBM cells from the cell growth inhibition by PGIA. Moreover, the formulation of PGIA in poly-(L)-lactic acid poly(ethylene glycol) polymeric nanoparticles improved its pharmacokinetics in mice, delivering PGIA to the brain. PGIA displays strong efficacy against GBM, crosses the blood-brain barrier when properly formulated, reaching the target tissue, and establishes cyclin D1 as an important molecular target. Thus, PGIA merits further evaluation as a potential therapeutic option for GBM.
authors.affiliation: Department of Family, Population and Preventive Medicine.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Bartels
authors.affiliation: Department of Medicine and.
authors.forename: George
authors.initials: G
authors.lastname: Mattheolabakis
authors.affiliation: Department of Family, Population and Preventive Medicine.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Vaeth
authors.affiliation: Department of Family, Population and Preventive Medicine.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: LaComb
authors.affiliation: Department of Family, Population and Preventive Medicine.
authors.forename: Ruixue
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Bioinformatics, Stony Brook University , Stony Brook, NY 11794-8175 , USA.
authors.forename: Jizu
authors.initials: J
authors.lastname: Zhi
authors.affiliation: Medicon Pharmaceuticals, Inc. , Stony Brook, NY 11790 , USA and.
authors.forename: Despina
authors.initials: D
authors.lastname: Komninou
authors.affiliation: Department of Medicine and.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794-8175, USA.
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
authors.affiliation: Department of Family, Population and Preventive Medicine.|Department of Medicine and.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794-8175, USA.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D005909:Glioblastoma / Q000473:pathology*; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice
chemical_list: D019938:Cyclin D1; D007052:Ibuprofen