Modulation of eIF5A Expression Using SNS01 Nanoparticles Inhibits NF-kappa B Activity and Tumor Growth in Murine Models of Multiple Myeloma

作者：Taylor Catherine A; Liu Zhongda; Tang Terence C; Zheng Qifa; Francis Sarah; Wang Tzann Wei; Ye Bin; Lust John A; Dondero Richard; Thompson John E^*

来源：Molecular Therapy, 2012, 20(7): 1305-1314.

DOI：10.1038/mt.2012.94

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-kappa B (NF-kappa B), 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 %26lt; 0.05) and RPMI 8226 (59% inhibition; P %26lt; 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. Received 22 November 2011; accepted 11 April 2012; advance online publication 15 May 2012. doi:10.1038/mt.2012.94

• 出版日期2012-7