Back to Journals » International Journal of Nanomedicine » Volume 10 » Issue 1

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

Authors Roy K, Kanwar RK, Krishnakumar S, Cheung CH, Kanwar JR

Received 7 September 2014

Accepted for publication 16 October 2014

Published 2 February 2015 Volume 2015:10(1) Pages 1019—1043

DOI https://doi.org/10.2147/IJN.S73916

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Thomas J Webster

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

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]

 

Other articles by this author:

Cissus quadrangularis inhibits IL-1β induced inflammatory responses on chondrocytes and alleviates bone deterioration in osteotomized rats via p38 MAPK signaling [Corrigendum]

Kanwar JR, Samarasinghe RM, Kumar K, Arya R, Sanjeev S, Zhou SF, Sasidharan S, Kanwar RK

Drug Design, Development and Therapy 2017, 11:2683-2684

Published Date: 12 September 2017

Theranostic multimodular potential of zinc-doped ferrite-saturated metal-binding protein-loaded novel nanocapsules in cancers

Kamalapuram SK, Kanwar RK, Roy K, Chaudhary R, Sehgal R, Kanwar JR

International Journal of Nanomedicine 2016, 11:1349-1366

Published Date: 1 April 2016

Biodegradable Eri silk nanoparticles as a delivery vehicle for bovine lactoferrin against MDA-MB-231 and MCF-7 breast cancer cells

Roy K, Patel YS, Kanwar RK, Rajkhowa R, Wang X, Kanwar JR

International Journal of Nanomedicine 2016, 11:25-44

Published Date: 21 December 2015

Neurobehavioral burden of multiple sclerosis with nanotheranostics

Sriramoju B, Kanwar RK, Kanwar JR

Neuropsychiatric Disease and Treatment 2015, 11:2675-2689

Published Date: 15 October 2015

Oral administration of encapsulated bovine lactoferrin protein nanocapsules against intracellular parasite Toxoplasma gondii

Anand N, Sehgal R, Kanwar RK, Dubey ML, Vasishta RK, Kanwar JR

International Journal of Nanomedicine 2015, 10:6355-6369

Published Date: 8 October 2015

Molecular targets in arthritis and recent trends in nanotherapy

Roy K, Kanwar RK, Kanwar JR

International Journal of Nanomedicine 2015, 10:5407-5420

Published Date: 26 August 2015

Effect of lactoferrin protein on red blood cells and macrophages: mechanism of parasite–host interaction

Anand N, Kanwar RK, Dubey ML, Vahishta RK, Sehgal R, Verma AK, Kanwar JR

Drug Design, Development and Therapy 2015, 9:3821-3835

Published Date: 27 July 2015

Cissus quadrangularis inhibits IL-1β induced inflammatory responses on chondrocytes and alleviates bone deterioration in osteotomized rats via p38 MAPK signaling

Kanwar JR, Samarasinghe RM, Kumar K, Arya R, Sharma S, Zhou SF, Sasidharan S, Kanwar RK

Drug Design, Development and Therapy 2015, 9:2927-2940

Published Date: 5 June 2015

Nanoformulated cell-penetrating survivin mutant and its dual actions

Sriramoju B, Kanwar RK, Kanwar JR

International Journal of Nanomedicine 2014, 9:3279-3298

Published Date: 10 July 2014

Neurological disorders and therapeutics targeted to surmount the blood–brain barrier

Kanwar JR, Sriramoju B, Kanwar RK

International Journal of Nanomedicine 2012, 7:3259-3278

Published Date: 9 July 2012

Readers of this article also read:

Perioperative management of hemophilia patients receiving total hip and knee arthroplasty: a complication report of two cases

Tateiwa T, Takahashi Y, Ishida T, Kubo K, Masaoka T, Shishido T, Sano K, Yamamoto K

Therapeutics and Clinical Risk Management 2015, 11:1383-1389

Published Date: 15 September 2015

Acquired hemophilia A: emerging treatment options

Janbain M, Leissinger CA, Kruse-Jarres R

Journal of Blood Medicine 2015, 6:143-150

Published Date: 8 May 2015

Optimal management of hemophilic arthropathy and hematomas

Lobet S, Hermans C, Lambert C

Journal of Blood Medicine 2014, 5:207-218

Published Date: 17 October 2014

The use of PEGylated liposomes in the development of drug delivery applications for the treatment of hemophilia

Rivka Yatuv, Micah Robinson, Inbal Dayan-Tarshish, et al

International Journal of Nanomedicine 2010, 5:581-591

Published Date: 6 August 2010

Crystallization after intravitreal ganciclovir injection

Pitipol Choopong, Nattaporn Tesavibul, Nattawut Rodanant

Clinical Ophthalmology 2010, 4:709-711

Published Date: 14 July 2010