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: Catherine A Taylor, Zhongda Liu, Terence C Tang, Qifa Zheng, Sarah Francis, Tzann-Wei Wang, Bin Ye, John A Lust, Richard Dondero, John E Thompson
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 20 Issue 7 Pg. 1305-14 (Jul 2012) ISSN: 1525-0024 [Electronic] United States
• PMID: 22588272 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Peptide Initiation Factors
• RNA, Small Interfering
• RNA-Binding Proteins
• eukaryotic translation initiation factor 5A

Topics

• Animals
• Cell Proliferation
• Mice
• Multiple Myeloma (genetics, metabolism, pathology, therapy)
• NF-kappa B (antagonists & inhibitors)
• Nanoparticles (therapeutic use)
• Peptide Initiation Factors (biosynthesis, genetics)
• Phosphorylation
• Plasmids
• RNA Interference
• RNA, Small Interfering (therapeutic use)
• RNA-Binding Proteins (biosynthesis, genetics)