Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy
Srijayaprakash B Uppada,1,* Terrianne Erickson,1 Luke Wojdyla,1 David N Moravec,1 Ziyuan Song,2 Jianjun Cheng,2 Neelu Puri1,* 1Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, 2Department of Materials Science and Engineering, University of Illinoi...
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doaj-911ca032815f487ebd7f4ba2c9e0926b2020-11-25T01:05:57ZengDove Medical PressInternational Journal of Nanomedicine1178-20132013-12-012014Issue 1435315302Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapyUppada SBErickson TWojdyla LMoravec DNSong ZCheng JPuri N Srijayaprakash B Uppada,1,* Terrianne Erickson,1 Luke Wojdyla,1 David N Moravec,1 Ziyuan Song,2 Jianjun Cheng,2 Neelu Puri1,* 1Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, 2Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA *These authors contributed equally to this work 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. Keywords: T-oligo, melanoma, senescence, angiogenesis, apoptosishttp://www.dovepress.com/novel-delivery-system-for-t-oligo-using-a-nanocomplex-formed-with-an-a-a15302 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Uppada SB Erickson T Wojdyla L Moravec DN Song Z Cheng J Puri N |
spellingShingle |
Uppada SB Erickson T Wojdyla L Moravec DN Song Z Cheng J Puri N Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy International Journal of Nanomedicine |
author_facet |
Uppada SB Erickson T Wojdyla L Moravec DN Song Z Cheng J Puri N |
author_sort |
Uppada SB |
title |
Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy |
title_short |
Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy |
title_full |
Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy |
title_fullStr |
Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy |
title_full_unstemmed |
Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy |
title_sort |
novel delivery system for t-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy |
publisher |
Dove Medical Press |
series |
International Journal of Nanomedicine |
issn |
1178-2013 |
publishDate |
2013-12-01 |
description |
Srijayaprakash B Uppada,1,* Terrianne Erickson,1 Luke Wojdyla,1 David N Moravec,1 Ziyuan Song,2 Jianjun Cheng,2 Neelu Puri1,* 1Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, 2Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA *These authors contributed equally to this work 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. Keywords: T-oligo, melanoma, senescence, angiogenesis, apoptosis |
url |
http://www.dovepress.com/novel-delivery-system-for-t-oligo-using-a-nanocomplex-formed-with-an-a-a15302 |
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