NF-κB Inhibition Suppresses Experimental Melanoma Lung Metastasis

Abstract

Background: Although novel therapeutic regimens for melanoma continue to emerge, the best current clinical response rate is still less than 60%. Moreover, antimelanoma treatments contribute to toxicities in other vital organs. In this study, we elucidate the therapeutic advantages of siRNA targeting melanoma NF-κB canonical signaling pathway with a peptide-based gene delivery nanoplex system. Methods and Results: In vitro treatment of melanoma B16-F10 cells was used to demonstrate delivery and efficacy of anti-NF-kB siRNA to cell cytoplasm with a 55 mn peptide-based gene delivery system. NF-κB (p65) knockdown was validated both at mRNA and protein levels by using RT2-PCR, western blot, and immunofluorescence cellular staining. Canonical p65 mRNA was reduced by 82% and p65 protein was reduced by 48%, which differed significantly from levels in control groups. In vivo treatment of a melanoma lung metastasis mouse model with 3-serial i.v. injections of p5RHH-p65 siRNA nanoparticles retarded growth of lung metastasis within one week by 76% (p=0.003) as compared to saline control treatments. Conclusion: Inhibition of melanoma NF-κB (p65) with systemically-delivered siRNA effectively impedes the growth and progression of experimental melanoma lung metastasis.

Targeting NF-κB with Nanotherapy in a Mouse Model of Adult T-Cell Leukemia/Lymphoma

“…We also detected some siRNA signal in the liver, lung, and brain, which may be due to lymphoma associated inflammation in central nervous system [ 57 , 58 , 59 , 60 , 61 ] and other organs. Because our previous studies have shown that this delivery system spares health brain [ 45 ], lung [ 50 ], and other organs/tissues, and is not cleared appreciably by a healthy liver [ 51 ], the present results support the observation that this nanomaterial permeates leaky vasculature associated with tumoral and inflammatory microenvironment.…”

“…In this study, we targeted both NF-κB canonical (p65) and noncanonical (p100) pathways in two distinct tumor models to define the utility of systemically delivered siRNA to exert focal control of ATLL at the tumor site. To this end, we recently reported a unique peptide-based nanoparticle design for the robust systemic delivery to cells of oligonucleotides that inhibit the translation of myriad mRNA’s including NF-κB [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. This peptide construct is based on selective modifications to a 26-amino acid cationic, amphipathic natural peptide, melittin.…”

Design of therapeutic biomaterials to control inflammation

“…Multi-shell nanoparticles containing a calcium phosphate core and PLGA/PEI layer allow intrarectal delivery of TNF, keratinocide-derived cytokine and interferon gamma-induced protein 10 siRNA to inhibit their gene expression and reduce intestinal inflammation in a mouse model 194 . Signal transducer and activator of transcription 1 siRNA, cyclooxygenase 2 siRNA and NF-κB siRNA can also be delivered for inflammation treatment 195 – 197 . Co-delivery of drugs and siRNA has shown better anti-inflammatory performance than drug or siRNA delivery alone 198 , 199 .…”

Defining novel causal SNPs and linked phenotypes at melanoma-associated loci

“…CASP8 has also been found to be overexpressed in a range of cancers including prostate and renal cancer where it is associated with a poor outcome. A potential explanation for this observation could be the role of CASP8 in increasing NF-κB levels, an event we ( 24 ) and others ( 25 , 26 ) have previously linked to enhanced melanoma cell growth. Thus, individuals who carry rs3769823-G may be predisposed to melanoma development via a role for this variant in influencing a switch from pro-apoptotic to anti-apoptotic functions of NF-κB.…”