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

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 (P < 0.05). 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 (P < 0.05). 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.

si-RNA-Mediated Silencing of ADRBK1 Gene Attenuates Breast Cancer Cell Proliferation

“…2 The silencing mechanism of RNAi is specifically mediated via small interference RNA (si-RNA) consisting of 19-23-nucleotide, double-stranded RNA duplexes that selectively knock down a target gene expression via degrading the mRNA and subsequently inhibiting the relative protein production. 3 Even though si-RNA shows a great potential to be used as a therapeutic tool, in vivo delivery of the specific si-RNA sequence to the target cells remains a challenge.…”

Nanoparticle-facilitated Intratumoral Delivery of Bcl-2/IGF-1R siRNAs and p53 Gene Synergistically Inhibits Tumor Growth in Immunocompetent Mice

“…J Nanomed Nanotechnol ISSN: 2157-7439 JNMNT, an open access journal Translational Nanoscience paclitaxel [52][53][54]. Being a survival factor IGF-1 could interfere with the actions of the cytotoxic agents by increasing proliferation and inhibiting apoptosis of drug-treated cancer cells through activation of MAPK and PI-3 kinase pathways [52].…”

“…Being a survival factor IGF-1 could interfere with the actions of the cytotoxic agents by increasing proliferation and inhibiting apoptosis of drug-treated cancer cells through activation of MAPK and PI-3 kinase pathways [52]. On the other hand, downregulation of Bcl-2, one of most important mediators of survival and drug resistance in most human cancers, would enable induction of doxorubicin-triggered autophagy by relieving its suppressor activity on Beclin-1 (an autophagy-promoting protein), which is physically bound and blocked by Bcl-2 [53]. In addition, overexpression of Bcl-2 generally protects cancer cells from paclitaxel-induced cell death by undergoing post-translation modification leading to mitochondrial apoptotic cell death [54,55].…”

Co-delivery of chemosensitizing siRNA and an anticancer agent via multiple monocomplexation-induced hydrophobic association

“…A previous study demonstrated sequential delivery of Bcl-2 siRNA and chemodrug, showing the enhanced efficacy of chemotherapy mediated by Bcl-2 silencing[25].Finally, the organic-soluble binary HMplex formed between Bcl-2 siRNA and BZT was further formulated into the ternary HMplex by encapsulating with micelles of a biocompatible polymeric surfactant, Pluronic F-68 (U.S. FDA approved as a local/i.v. injectable pharmaceutical ingredient), which would improve the complex stability as well as the efficiencies of cell penetration and in vivo delivery[26].The colloidal size is an important parameter that governs the tumor-targeting efficiency of nanotherapeutics.…”