Halder, J, Kamat, AA, Landen, CN Jr., Han, LY, Lutgendorf, SK, Lin, YG et al.. Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy. Clin Cancer Res 12: 4916-4924

Department of Psychology, University of Iowa, Iowa City, Iowa, United States
Clinical Cancer Research (Impact Factor: 8.72). 08/2006; 12(16):4916-24. DOI: 10.1158/1078-0432.CCR-06-0021
Source: PubMed


Focal adhesion kinase (FAK) plays a critical role in ovarian cancer cell survival and in various steps in the metastatic cascade. Based on encouraging in vitro results with FAK silencing, we examined the in vivo therapeutic potential of this approach using short interfering RNA (siRNA) in the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC).
Therapy experiments of FAK siRNA with or without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8MDR in nude mice. Additional experiments with a cisplatin-resistant cell line (A2780-CP20) were also done. Assessments of angiogenesis (CD31), cell proliferation (proliferating cell nuclear antigen), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) were done using immunohistochemical analysis.
A single dose of FAK siRNA-DOPC was highly effective in reducing in vivo FAK expression for up to 4 days as assayed by Western blot and immunohistochemical analysis. Therapy experiments were started 1 week after injection of the ovarian cancer cells. Treatment with FAK siRNA-DOPC (150 mug/kg twice weekly) reduced mean tumor weight by 44% to 72% in the three cell lines compared with the control group (Ps < 0.05 for HeyA8, A2780-CP20, and SKOV3ip1). When FAK siRNA-DOPC was combined with docetaxel, there was even greater reduction in mean tumor weight in all models (all Ps < 0.05). Similar results were observed in combination with cisplatin. Treatment with FAK siRNA-DOPC plus docetaxel resulted in decreased microvessel density, decreased expression of vascular endothelial growth factor and matrix metalloproteinase-9, and increased apoptosis of tumor-associated endothelial cells and tumor cells.
Taken together, these findings suggest that FAK siRNA-DOPC plus docetaxel or platinum might be a novel therapeutic approach against ovarian cancer.

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    • "DOPC-encapsulated siRNA targeting the oncoprotein EphA2 was highly effective in reducing EphA2 expression 48 h after administration of a single dose in an orthotopic model of ovarian carcinoma [16]. Treatment with DOPC-encapsulated siRNA via intravenous or intraperitoneal injections was highly effective in reducing both in vivo expression of target genes (e.g., EphA2, FAK, neuropilin-2, or IL-8) and tumor weight in mouse models of different human cancers [16] [17] [18] [19]. In 2012, M.D. Anderson Cancer Center initiated a phase I dose-escalation trial for neutral liposome (DOPC) targeting of Eph2 in patients with advanced, recurrent cancer ( "
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    • "To determine the in vivo significance of PELP1 in breast cancer progression, siRNA in a nanoliposomal formulation (PELP1-siRNA-DOPC) was used to silence PELP1 gene expression. Several published studies have validated the delivery and therapeutic efficacy of DOPC-based siRNA nanoliposomes to knock down expression of specific genes in vivo [23,27,28]. Adult female athymic nu/nu mice received a 17β-estradiol pellet (0.72 mg/pellet, 60-day release) 1 week prior to subcutaneous injection of MCF-7 breast cancer model cells (5×106 cells) into both flanks. "
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    • "Therefore, careful selection of lipids and formulation strategies may help reduce or eliminate toxicity and potential adverse effects [6]. One of the most important advances in the siRNA delivery field has been the development of neutral 1,2- dioleoyl-sn-glycero-3-phosphatidylcholine-(DOPC-) based nanoliposomes [19] [20] [21] [22]. These nanoliposomes can deliver siRNA in vivo into tumour cells 10-and 30-fold more effectively than cationic liposomes (DOTAP) and naked siRNA, respectively [23]. "
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