title: CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy.
abstract: The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States. Electronic address: Emily.Carifi@nih.gov.
authors.forename: Emily
authors.initials: E
authors.lastname: Foran
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States; Department of Neuroscience, Brown University, United States.
authors.forename: Deborah Y
authors.initials: DY
authors.lastname: Kwon
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Nofziger
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
authors.forename: Eveline S
authors.initials: ES
authors.lastname: Arnold
authors.affiliation: CE Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Services, United States.
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D000069286:Bortezomib / Q000378:metabolism*; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014162:Transfection
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; C476399:Cd44 protein, mouse; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D011804:Quinolines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C402343:tariquidar
keywords: Blood brain barrier (BBB); Bortezomib; P-glycoprotein (P-gp); Proteasome; Spinal muscular atrophy (SMA); Survival motor neuron (SMN); Tariquidar