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

Roy, Kislay, Kanwar, Rupinder K., Krishnakumar, Subramanian, Cheung, Chun Hei Antonio and Kanwar, Jagat R. 2015, Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model, International journal of nanomedicine, vol. 10, pp. 1019-1043, doi: 10.2147/IJN.S73916.

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Title Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
Author(s) Roy, Kislay
Kanwar, Rupinder K.
Krishnakumar, Subramanian
Cheung, Chun Hei Antonio
Kanwar, Jagat R.ORCID iD for Kanwar, Jagat R. orcid.org/0000-0003-3728-9568
Journal name International journal of nanomedicine
Volume number 10
Start page 1019
End page 1043
Total pages 25
Publisher Dove Medical Press
Place of publication Auckland, N. Z.
Publication date 2015
ISSN 1176-9114
1178-2013
Keyword(s) chitosan
cytotoxicity
mucoadhesive
nanoparticle
xenograft
Science & Technology
Life Sciences & Biomedicine
Nanoscience & Nanotechnology
Pharmacology & Pharmacy
Science & Technology - Other Topics
CHITOSAN NANOPARTICLES
TARGETING SURVIVIN
PROSTATE-CANCER
IN-VITRO
EXPRESSION
DELIVERY
DEATH
DRUG
PROLIFERATION
DEGRADATION
Summary 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.
Language eng
DOI 10.2147/IJN.S73916
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2015, Dove Medical Press
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30072429

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.