title: Proteasome regulator marizomib (NPI-0052) exhibits prolonged inhibition, attenuated efflux, and greater cytotoxicity than its reversible analogs.
abstract: The present study was undertaken to compare the cellular transport characteristics of [(3)H]NPI-0052 (1R,4R,5S)-4-(2-chloroethyl)-1-((S)-((S)-cyclohex-2-enyl)(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione (marizomib; salinosporamide A) and [(3)H]NPI-0047 (1R,4R, 5S)-1-((S)-((S)-cyclohex-2-enyl)(hydroxy)methyl)-4-ethyl-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione in RPMI 8226 multiple myeloma and PC-3 prostate adenocarcinoma cells to determine whether these properties explain differences in the cytotoxic potencies of these chemical analogs. The results indicate that marizomib, which possesses a chemical-leaving group, is more cytotoxic to both cell lines and inhibits proteasome activity more completely at lower concentrations than NPI-0047, a nonleaving-group analog. Moreover, it was found that both compounds accumulate in these cells by simple diffusion and the same carrier-mediated transport system. Although the rate of uptake is similar, the cellular efflux, which does not seem to be mediated by a major ATP-binding cassette (ABC)-efflux transporter, is more rapid for NPI-0047 than for marizomib. Experiments revealed that the irreversible binding of marizomib to the proteasome is responsible for its slower efflux, longer duration of action, and greater cytotoxicity compared with NPI-0047. The discovery that major ABC transporters of the multidrug resistance-associated protein family do not seem to be involved in the accumulation or removal of these agents suggests they may not be affected by multidrug resistance mechanisms during prolonged administration.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Obaidat
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weiss
authors.forename: Brett
authors.initials: B
authors.lastname: Wahlgren
authors.forename: Rama R
authors.initials: RR
authors.lastname: Manam
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Macherla
authors.forename: Katherine
authors.initials: K
authors.lastname: McArthur
authors.forename: Ta-Hsiang
authors.initials: TH
authors.lastname: Chao
authors.forename: Michael A
authors.initials: MA
authors.lastname: Palladino
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Lloyd
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Potts
authors.forename: Salvatore J
authors.initials: SJ
authors.lastname: Enna
authors.forename: Saskia T C
authors.initials: ST
authors.lastname: Neuteboom
authors.forename: Bruno
authors.initials: B
authors.lastname: Hagenbuch
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007769:Lactams / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007769:Lactams; D007783:Lactones; D011758:Pyrroles; C475865:marizomib; D046988:Proteasome Endopeptidase Complex