Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model

Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model

Kislay Roy,1 Rupinder K Kanwar,1 Subramanian Krishnakumar,2,3 Chun Hei Antonio Cheung,4 Jagat R Kanwar1 1Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Molecular and Medical Research (MMR) Strategic Research Centre, School of Medicine (SoM), Faculty of H...

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Autores principales: Roy K, Kanwar RK, Krishnakumar S, Cheung CH, Kanwar JR
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Lenguaje:EN
Publicado: Dove Medical Press 2015
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Medicine (General)
R5-920
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spelling oai:doaj.org-article:1bcbf37790d246138ee4845c611198802021-12-02T07:13:42ZCompetitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model1178-2013https://doaj.org/article/1bcbf37790d246138ee4845c611198802015-02-01T00:00:00Zhttp://www.dovepress.com/competitive-inhibition-of-survivin-using-anbspcell-permeable-recombina-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013 Kislay Roy,1 Rupinder K Kanwar,1 Subramanian Krishnakumar,2,3 Chun Hei Antonio Cheung,4 Jagat R Kanwar1 1Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Molecular and Medical Research (MMR) Strategic Research Centre, School of Medicine (SoM), Faculty of Health, Deakin University, Waurn Ponds, VIC, Australia; 2Department of Nanobiotechnology, 3Larsen & Toubro (L&T) Ocular Pathology Department, Vision Research Foundation, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Chennai, India; 4Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China Abstract: Endogenous survivin expression has been related with cancer survival, drug resistance, and metastasis. Therapies targeting survivin have been shown to significantly inhibit tumor growth and recurrence. We found out that a cell-permeable dominant negative survivin (SurR9-C84A, referred to as SR9) competitively inhibited endogenous survivin and blocked the cell cycle at the G1/S phase. Nanoencapsulation in mucoadhesive chitosan nanoparticles (CHNP) substantially increased the bioavailability and serum stability of SR9. The mechanism of nanoparticle uptake was studied extensively in vitro and in ex vivo models. Our results confirmed that CHNP–SR9 protected primary cells from autophagy and successfully induced tumor-specific apoptosis via both extrinsic and intrinsic apoptotic pathways. CHNP–SR9 significantly reduced the tumor spheroid size (three-dimensional model) by nearly 7-fold. Effects of SR9 and CHNP–SR9 were studied on 35 key molecules involved in the apoptotic pathway. Highly significant (4.26-fold, P≤0.005) reduction in tumor volume was observed using an in vivo mouse xenograft colon cancer model. It was also observed that net apoptotic (6.25-fold, P≤0.005) and necrotic indexes (3.5-fold, P≤0.05) were comparatively higher in CHNP–SR9 when compared to void CHNP and CHNP–SR9 internalized more in cancer stem cells (4.5-fold, P≤0.005). We concluded that nanoformulation of SR9 did not reduce its therapeutic potential; however, nanoformulation provided SR9 with enhanced stability and better bioavailability. Our study presents a highly tumor-specific protein-based cancer therapy that has several advantages over the normally used chemotherapeutics. Keywords: nanoparticle, chitosan, mucoadhesive, cytotoxicity, xenograftRoy KKanwar RKKrishnakumar SCheung CHKanwar JRDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2015, Iss default, Pp 1019-1043 (2015)
institution DOAJ
collection DOAJ
language EN
topic Medicine (General)
R5-920
spellingShingle Medicine (General)
R5-920
Roy K
Kanwar RK
Krishnakumar S
Cheung CH
Kanwar JR
Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
description Kislay Roy,1 Rupinder K Kanwar,1 Subramanian Krishnakumar,2,3 Chun Hei Antonio Cheung,4 Jagat R Kanwar1 1Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Molecular and Medical Research (MMR) Strategic Research Centre, School of Medicine (SoM), Faculty of Health, Deakin University, Waurn Ponds, VIC, Australia; 2Department of Nanobiotechnology, 3Larsen & Toubro (L&T) Ocular Pathology Department, Vision Research Foundation, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Chennai, India; 4Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China Abstract: Endogenous survivin expression has been related with cancer survival, drug resistance, and metastasis. Therapies targeting survivin have been shown to significantly inhibit tumor growth and recurrence. We found out that a cell-permeable dominant negative survivin (SurR9-C84A, referred to as SR9) competitively inhibited endogenous survivin and blocked the cell cycle at the G1/S phase. Nanoencapsulation in mucoadhesive chitosan nanoparticles (CHNP) substantially increased the bioavailability and serum stability of SR9. The mechanism of nanoparticle uptake was studied extensively in vitro and in ex vivo models. Our results confirmed that CHNP–SR9 protected primary cells from autophagy and successfully induced tumor-specific apoptosis via both extrinsic and intrinsic apoptotic pathways. CHNP–SR9 significantly reduced the tumor spheroid size (three-dimensional model) by nearly 7-fold. Effects of SR9 and CHNP–SR9 were studied on 35 key molecules involved in the apoptotic pathway. Highly significant (4.26-fold, P≤0.005) reduction in tumor volume was observed using an in vivo mouse xenograft colon cancer model. It was also observed that net apoptotic (6.25-fold, P≤0.005) and necrotic indexes (3.5-fold, P≤0.05) were comparatively higher in CHNP–SR9 when compared to void CHNP and CHNP–SR9 internalized more in cancer stem cells (4.5-fold, P≤0.005). We concluded that nanoformulation of SR9 did not reduce its therapeutic potential; however, nanoformulation provided SR9 with enhanced stability and better bioavailability. Our study presents a highly tumor-specific protein-based cancer therapy that has several advantages over the normally used chemotherapeutics. Keywords: nanoparticle, chitosan, mucoadhesive, cytotoxicity, xenograft
format article
author Roy K
Kanwar RK
Krishnakumar S
Cheung CH
Kanwar JR
author_facet Roy K
Kanwar RK
Krishnakumar S
Cheung CH
Kanwar JR
author_sort Roy K
title Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
title_short Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
title_full Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
title_fullStr Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
title_full_unstemmed Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
title_sort competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
publisher Dove Medical Press
publishDate 2015
url https://doaj.org/article/1bcbf37790d246138ee4845c61119880
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