title: Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy.
abstract: Oligonucleotides homologous to 3'-telomere overhang (T-oligos) trigger inherent telomere-based DNA damage responses mediated by p53 and/or ATM and induce senescence or apoptosis in various cancerous cells. However, T-oligo has limited stability in vivo due to serum and intracellular nucleases. To develop T-oligo as an innovative, effective therapeutic drug and to understand its mechanism of action, we investigated the antitumor effects of T-oligo or T-oligo complexed with a novel cationic alpha helical peptide, PVBLG-8 (PVBLG), in a p53 null melanoma cell line both in vitro and in vivo. The uptake of T-oligo by MM-AN cells was confirmed by immunofluorescence, and fluorescence-activated cell sorting analysis indicated that the T-oligo-PVBLG nanocomplex increased uptake by 15-fold. In vitro results showed a 3-fold increase in MM-AN cell growth inhibition by the T-oligo-PVBLG nanocomplex compared with T-oligo alone. Treatment of preformed tumors in immunodeficient mice with the T-oligo-PVBLG nanocomplex resulted in a 3-fold reduction in tumor volume compared with T-oligo alone. This reduction in tumor volume was associated with decreased vascular endothelial growth factor expression and induction of thrombospondin-1 expression and apoptosis. Moreover, T-oligo treatment downregulated procaspase-3 and procaspase-7 and increased catalytic activity of caspase-3 by 4-fold in MM-AN cells. Furthermore, T-oligo induced a 10-fold increase of senescence and upregulated the melanoma tumor-associated antigens MART-1, tyrosinase, and thrombospondin-1 in MM-AN cells, which are currently being targeted for melanoma immunotherapy. Interestingly, siRNA-mediated knockdown of p73 (4-10-fold) abolished this upregulation of tumor-associated antigens. In summary, we suggest a key role of p73 in mediating the anticancer effects of T-oligo and introduce a novel nanoparticle, the T-oligo-PVBLG nanocomplex, as an effective anticancer therapeutic.
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, USA.
authors.forename: Srijayaprakash B
authors.initials: SB
authors.lastname: Uppada
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, USA.
authors.forename: Terrianne
authors.initials: T
authors.lastname: Erickson
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Wojdyla
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Moravec
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, USA.
authors.forename: Neelu
authors.initials: N
authors.lastname: Puri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004338:Drug Combinations; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D009841:Oligonucleotides / Q000235:genetics / Q000627:therapeutic use*; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D053769:Nanocapsules; D009841:Oligonucleotides; D010455:Peptides
keywords: T-oligo; angiogenesis; apoptosis; melanoma; senescence