title: Modulation of eIF5A expression using SNS01 nanoparticles inhibits NF-κB activity and tumor growth in murine models of multiple myeloma.
abstract: Despite recent advances in the first-line treatment of multiple myeloma, almost all patients eventually experience relapse with drug-resistant disease. New therapeutic modalities are needed, and to this end, SNS01, a therapeutic nanoparticle, is being investigated for treatment of multiple myeloma. The antitumoral activity of SNS01 is based upon modulation of eukaryotic translation initiation factor 5A (eIF5A), a highly conserved protein that is involved in many cellular processes including proliferation, apoptosis, differentiation and inflammation. eIF5A is regulated by post-translational hypusine modification, and overexpression of hypusination-resistant mutants of eIF5A induces apoptosis in many types of cancer cells. SNS01 is a polyethylenimine (PEI)-based nanoparticle that contains both a B-cell-specific expression plasmid expressing a non-hypusinable mutant of eIF5A and a small interfering RNA (siRNA) which depletes endogenous hypusinated eIF5A. Reducing hypusine-modified eIF5A levels was found to inhibit phosphorylation and activity of ERK MAPK and nuclear factor-κB (NF-κB), and thus sensitize myeloma cells to apoptosis resulting from transfection of a plasmid expressing eIF5A(K50R). SNS01 exhibited significant antitumoral activity in both KAS-6/1 (95% inhibition; P < 0.05) and RPMI 8226 (59% inhibition; P < 0.05) multiple myeloma xenograft models following systemic administration. These results highlight the potential of using this approach as a new therapeutic strategy for multiple myeloma.
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Taylor
authors.forename: Zhongda
authors.initials: Z
authors.lastname: Liu
authors.forename: Terence C
authors.initials: TC
authors.lastname: Tang
authors.forename: Qifa
authors.initials: Q
authors.lastname: Zheng
authors.forename: Sarah
authors.initials: S
authors.lastname: Francis
authors.forename: Tzann-Wei
authors.initials: TW
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: John A
authors.initials: JA
authors.lastname: Lust
authors.forename: Richard
authors.initials: R
authors.lastname: Dondero
authors.forename: John E
authors.initials: JE
authors.lastname: Thompson
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D053758:Nanoparticles / Q000627:therapeutic use*; D010448:Peptide Initiation Factors / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D010957:Plasmids; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D016328:NF-kappa B; D010448:Peptide Initiation Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A