Intravenous siRNA Silencing of Survivin Enhances Activity of Mitomycin C in Human Bladder RT4 Xenografts

Minjian Cui; Jessie L.-S Au; M. Guillaume Wientjes; Michael A O'Donnell; Kevin R Loughlin; Ze Lu

doi:10.1016/j.juro.2015.02.036

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Intravenous siRNA Silencing of Survivin Enhances Activity of Mitomycin C in Human Bladder RT4 Xenografts

Journal article

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Peer reviewed

Intravenous siRNA Silencing of Survivin Enhances Activity of Mitomycin C in Human Bladder RT4 Xenografts

Minjian Cui, Jessie L.-S Au, M. Guillaume Wientjes, Michael A O'Donnell, Kevin R Loughlin and Ze Lu

The Journal of urology, Vol.194(1), pp.230-237

07/2015

DOI: 10.1016/j.juro.2015.02.036

PMCID: PMC4512300

PMID: 25681288

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Abstract

Survivin inhibits apoptosis and enables tumor cells to escape from therapy induced senescence. High survivin expression is associated with bladder cancer aggressiveness and recurrence. We evaluated whether survivin expression is reduced by siRNA and whether survivin silencing would enhance mitomycin C activity in human RT4 bladder transitional cell tumors in vitro and in vivo. We assessed the effectiveness of siRNA therapy using 2 newly developed pegylated cationic liposome carriers, PCat and PPCat. Each has a fusogenic lipid to destabilize the endosomal membrane. PPCat further contains paclitaxel to enhance in vivo delivery and transfection of survivin siRNA. In vitro antitumor activity was evaluated by short-term MTT and long-term clonogenicity cytotoxicity assays. In vivo intravenous therapy was assessed in mice bearing subcutaneous tumors. Nontarget siRNA showed no antitumor activity in vitro or in vivo. Treatment of cultured cells with mitomycin C at a 50% cytotoxic concentration enhanced survivin mRNA and protein levels. Adding PPCat or PCat containing survivin siRNA reversed survivin induction and enhanced mitomycin C activity (p <0.05). In tumor bearing mice single agent mitomycin C delayed tumor growth and almost tripled the survivin protein level in residual tumors. Adding PPCat-survivin siRNA, which alone resulted in a minor survivin decrease of less than 10%, completely reversed mitomycin C induced survivin and enhanced mitomycin C activity (p <0.05). Results indicate that there is effective in vivo survivin silencing and synergism between mitomycin C and PPCat-survivin siRNA. This combination represents a potentially useful chemo-gene therapy for bladder cancer.

RNA

genetic therapy

mitomycin

urinary bladder neoplasms

small interfering

human

BIRC5 protein

Details

Title: Subtitle: Intravenous siRNA Silencing of Survivin Enhances Activity of Mitomycin C in Human Bladder RT4 Xenografts
Creators: Minjian Cui - Optimum Therapeutics LLC, San Diego, California
Jessie L.-S Au - Optimum Therapeutics LLC, San Diego, California
M. Guillaume Wientjes - Optimum Therapeutics LLC, San Diego, California
Michael A O'Donnell - University of Iowa, Iowa City, Iowa
Kevin R Loughlin - Brigham and Women's Hospital, Boston, Massachusetts
Ze Lu - Optimum Therapeutics LLC, San Diego, California
Resource Type: Journal article
Publication Details: The Journal of urology, Vol.194(1), pp.230-237
DOI: 10.1016/j.juro.2015.02.036
PMID: 25681288
PMCID: PMC4512300
NLM abbreviation: J Urol
ISSN: 0022-5347
eISSN: 1527-3792
Publisher: Elsevier Inc
Grant note: Department of Health and Human Services R43TR000356 / National Center for Advancing Translational Sciences National Institutes of Health R01CA158300 / National Cancer Institute
Language: English
Date published: 07/2015
Academic Unit: Urology
Record Identifier: 9984051585202771

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