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.

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

“…High expression levels of hypusinated eIF5A have been associated with activation of oncogenes and with malignant transformation of hematopoietic cells. A polyethylenimine-based NP containing anti-eIF5A siRNA efficiently reduced eIF5A mRNA and protein expression levels, which sensitized MM cells to apoptosis [53]. In this study, inhibition of eIF5A using targeted siRNA, but not negative control siRNA, also resulted in downregulation of ERK/MAPK and NF-kB, which significantly slowed down the myeloma growth in subcutaneous xenograft mouse models.…”

“…In this study, inhibition of eIF5A using targeted siRNA, but not negative control siRNA, resulted in downregulation of ERK/MAPK and NF-kB, which significantly slowed down the myeloma growth in subcutaneous xenograft mouse models [53] the most common chromosomal abnormalities in MM (~70% of alterations) along with deletions of chromosome 13 [40]. In addition, abnormalities of chromosomes 17 and 18 involving the p53 and c-MYC genes are generally considered to be less frequent events (i.e., secondary events) but carry a poor prognosis [40].…”

“…In addition, it was reported that eukaryotic translation initiation factor 5A (eIF5A), a highly conserved protein is regulated by post-translational hypusine modification, which is involved in many cellular processes including proliferation, apoptosis, differentiation and inflammation [53]. High expression levels of hypusinated eIF5A have been associated with activation of oncogenes and with malignant transformation of hematopoietic cells.…”

Doxorubicin-Hyaluronan Conjugated Super-Paramagnetic Iron Oxide Nanoparticles (DOX-HA-SPION) Enhanced Cytoplasmic Uptake of Doxorubicin and Modulated Apoptosis, IL-6 Release and NF-kappaB Activity in Human MDA-MB-231 Breast Cancer Cells

“…Moreover, activation of NF-κB has also been shown to enhance production of cytokines (IL-6), inhibit apoptosis as well as contribute to drug resistance. 98 …”

The spermidine analogue GC7 (N1-guanyl-1,7-diamineoheptane) induces autophagy through a mechanism not involving the hypusination of eIF5A

“…It has also been implicated in the regulation of mRNA turnover (Zuk and Jacobson 1998), cell proliferation (Park et al 1993, differentiation (Schnier et al 1991;Park et al 2010), inflammation, (Moore et al 2008) and apoptosis (Taylor et al 2013). Interestingly, the pro-apoptotic function of eIF5A-1 appears to be the only eIF5A activity which is independent from hypusine modification (Taylor et al 2007(Taylor et al , 2012Sun et al 2010). Growing evidence indicates that apoptosis induction is often associated with decreased autophagy, underlying the existence of an interplay between these two important cellular events (Fimia and Piacentini 2010).…”