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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Autores principales:	Uppada SB, Erickson T, Wojdyla L, Moravec DN, Song Z, Cheng J, Puri N
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2013
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/911ca032815f487ebd7f4ba2c9e0926b
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spelling	oai:doaj.org-article:911ca032815f487ebd7f4ba2c9e0926b2021-12-02T03:54:00ZNovel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy1178-2013https://doaj.org/article/911ca032815f487ebd7f4ba2c9e0926b2013-12-01T00:00:00Zhttp://www.dovepress.com/novel-delivery-system-for-t-oligo-using-a-nanocomplex-formed-with-an-a-a15302https://doaj.org/toc/1178-2013 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, apoptosisUppada SBErickson TWojdyla LMoravec DNSong ZCheng JPuri NDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2014, Iss Issue 1, Pp 43-53 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 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
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
format	article
author	Uppada SB Erickson T Wojdyla L Moravec DN Song Z Cheng J Puri N
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
publishDate	2013
url	https://doaj.org/article/911ca032815f487ebd7f4ba2c9e0926b
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Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy

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