Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and͞or legs. We also show that the siRNA͞ atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3-hydroxykinase p110-␣-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-␣ levels was not associated with the in vivo administration of the siRNA͞atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.bone metastasis ͉ prostate cancer R NA interference (RNAi) induced by small interfering RNA (siRNA) has recently emerged as a powerful technique that is capable of suppressing expression of individual genes with a high degree of specificity (1). The technique has been used for studies of gene function in vivo, primarily in mice. The first demonstration of RNAi-mediated repression in an adult animal showed effective repression of a luciferase reporter gene after hydrodynamic transfection of siRNA expression plasmids into mouse liver (2, 3). Subsequent studies have delivered siRNA by various methods, including viral vector-mediated delivery (4, 5) and lipid-based delivery (6, 7). A more recent study showed that chemically modified siRNAs can silence an endogenous gene after i.v. injection in mice (8). These findings provide hope for using RNAi technology in disease control.Many studies have used siRNAs as an experimental tool to dissect the cellular pathways that lead to uncontrolled cell proliferation and cancer. To develop siRNAs for cancer therapy, several researchers have investigated them in animal models (9-13). However, reports of RNAi-delivery strategies for bonemetastatic cancer are very limited. For example, in advanced prostate cancer, the sites most frequently affected by metastasis are the bones and regional lymph nodes. Patients with these metastases suffer pain and low limb edema, making it extremely important to explore avenues of treating such bone metastases.We previously demonstrated the efficacy of atelocollagen for delivery of nucleotides, such as plasmid DNA and antisense oligonucleotides, in vitro and in vivo (14)(15)(16)(17)(18)(19). Recently, we also reported that a...
Silencing gene expression by siRNAs is rapidly becoming a powerful tool for the genetic analysis of mammalian cells. However, the rapid degradation of siRNA and the limited duration of its action call for an efficient delivery technology. Accordingly, we describe here that Atelocollagen complexed with siRNA is resistant to nucleases and is efficiently transduced into cells, thereby allowing long-term gene silencing. Site-specific in vivo administration of an anti-luciferase siRNA/Atelocollagen complex reduced luciferase expression in a xenografted tumor. Furthermore, Atelocollagen-mediated transfer of siRNA in vivo showed efficient inhibition of tumor growth in an orthotopic xenograft model of a human non-seminomatous germ cell tumor. Thus, for clinical applications of siRNA, an Atelocollagen-based non-viral delivery method could be a reliable approach to achieve maximal function of siRNA in vivo.
Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribophorin [corrected] II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference-based therapeutics against drug resistance.
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