Back to Search
Start Over
Therapeutic Silencing of Bcl-2 by Systemically Administered siRNA Nanotherapeutics Inhibits Tumor Growth by Autophagy and Apoptosis and Enhances the Efficacy of Chemotherapy in Orthotopic Xenograft Models of ER (−) and ER (+) Breast Cancer
- Source :
- Molecular Therapy. Nucleic Acids, Molecular Therapy: Nucleic Acids, Vol 2, Iss C (2013)
- Publication Year :
- 2013
- Publisher :
- Nature Publishing Group, 2013.
-
Abstract
- Bcl-2 is overexpressed in about a half of human cancers and 50-70% of breast cancer patients, thereby conferring resistance to conventional therapies and making it an excellent therapeutic target. Small interfering RNA (siRNA) offers novel and powerful tools for specific gene silencing and molecularly targeted therapy. Here, we show that therapeutic silencing of Bcl-2 by systemically administered nanoliposomal (NL)-Bcl-2 siRNA (0.15 mg siRNA/kg, intravenous) twice a week leads to significant antitumor activity and suppression of growth in both estrogen receptor-negative (ER(-)) MDA-MB-231 and ER-positive (+) MCF7 breast tumors in orthotopic xenograft models (P0.05). A single intravenous injection of NL-Bcl-2-siRNA provided robust and persistent silencing of the target gene expression in xenograft tumors. NL-Bcl-2-siRNA treatment significantly increased the efficacy of chemotherapy when combined with doxorubicin in both MDA-MB-231 and MCF-7 animal models (P0.05). NL-Bcl-2-siRNA treatment-induced apoptosis and autophagic cell death, and inhibited cyclin D1, HIF1α and Src/Fak signaling in tumors. In conclusion, our data provide the first evidence that in vivo therapeutic targeting Bcl-2 by systemically administered nanoliposomal-siRNA significantly inhibits growth of both ER(-) and ER(+) breast tumors and enhances the efficacy of chemotherapy, suggesting that therapeutic silencing of Bcl-2 by siRNA is a viable approach in breast cancers.Molecular Therapy-Nucleic Acids (2013) 2, e121; doi:10.1038/mtna.2013.45; published online 10 September 2013.
- Subjects :
- Programmed cell death
Small interfering RNA
autophagy
medicine.medical_treatment
Estrogen receptor
nanotherapeutics
Pharmacology
chemotherapy
Targeted therapy
03 medical and health sciences
gene silencing
0302 clinical medicine
Cyclin D1
Breast cancer
breast cancer
Drug Discovery
medicine
Gene silencing
Doxorubicin
Bcl-2
030304 developmental biology
0303 health sciences
business.industry
lcsh:RM1-950
apoptosis
medicine.disease
3. Good health
lcsh:Therapeutics. Pharmacology
030220 oncology & carcinogenesis
liposome
Molecular Medicine
Original Article
nanoparticles
programmed cell deathsiRNA
business
medicine.drug
estrogen receptor
Subjects
Details
- Language :
- English
- ISSN :
- 21622531
- Volume :
- 2
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy. Nucleic Acids
- Accession number :
- edsair.doi.dedup.....d145c1fe4a59ff8ff66c63862a4a85de