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siRNA Lipid Nanoparticle Potently Silences Clusterin and Delays Progression When Combined with Androgen Receptor Cotargeting in Enzalutamide-Resistant Prostate Cancer.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Nov 01; Vol. 21 (21), pp. 4845-55. Date of Electronic Publication: 2015 Jun 23. - Publication Year :
- 2015
-
Abstract
- Purpose: Lipid nanoparticle (LNP) formulations facilitate tumor uptake and intracellular processing through an enhanced permeation and retention effect (EPR), and currently multiple products are undergoing clinical evaluation. Clusterin (CLU) is a cytoprotective chaperone induced by androgen receptor (AR) pathway inhibition to facilitate adaptive survival pathway signaling and treatment resistance. In our study, we investigated the efficacy of siRNA tumor delivery using LNP systems in an enzalutamide-resistant (ENZ-R) castration-resistant prostate cancer (CRPC) model.<br />Experimental Design: Gene silencing of a luciferase reporter gene in the PC-3M-luc stable cell line was first assessed in subcutaneous and metastatic PC-3 xenograft tumors. Upon validation, the effect of LNP siRNA targeting CLU in combination with AR antisense oligonucleotides (ASO) was assessed in ENZ-R CRPC LNCaP in vitro and in vivo models.<br />Results: LNP LUC-siRNA silenced luciferase expression in PC-3M-luc subcutaneous xenograft and metastatic models. LNP CLU-siRNA potently suppressed CLU and AR ASO-induced CLU and AKT and ERK phosphorylation in ENZ-R LNCaP cells in vitro, more potently inhibiting ENZ-R cell growth rates and increased apoptosis when compared with AR-ASO monotherapy. In subcutaneous ENZ-R LNCaP xenografts, combinatory treatment of LNP CLU-siRNA plus AR-ASO significantly suppressed tumor growth and serum PSA levels compared with LNP LUC-siRNA (control) and AR-ASO.<br />Conclusions: LNP siRNA can silence target genes in vivo and enable inhibition of traditionally non-druggable genes like CLU and other promising cotargeting approaches in ENZ-R CRPC therapeutics.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Apoptosis genetics
Benzamides
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Disease Progression
Drug Resistance, Neoplasm
Gene Expression
Genes, Reporter
Humans
Male
Mice
Molecular Imaging methods
Neoplasm Metastasis
Nitriles
Oligonucleotides, Antisense genetics
Phenylthiohydantoin analogs & derivatives
Phenylthiohydantoin pharmacology
Prostatic Neoplasms, Castration-Resistant genetics
Prostatic Neoplasms, Castration-Resistant pathology
Xenograft Model Antitumor Assays
Clusterin genetics
Gene Silencing
Lipids
Nanoparticles
Prostatic Neoplasms genetics
Prostatic Neoplasms pathology
RNA, Small Interfering genetics
Receptors, Androgen genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 21
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 26106075
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-0866