Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy.

TitleFocal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy.
Publication TypeJournal Article
Year of Publication2006
AuthorsHalder J, Kamat AA, Landen CN, Han LY, Lutgendorf SK, Lin YG, Merritt WM, Jennings NB, Chavez-Reyes A, Coleman RL, Gershenson DM, Schmandt R, Cole SW, Lopez-Berestein G, Sood AK
JournalClin Cancer Res
Volume12
Issue16
Pagination4916-24
Date Published2006 Aug 15
ISSN1078-0432
KeywordsAnimals, Apoptosis, Cell Proliferation, Down-Regulation, Female, Focal Adhesion Protein-Tyrosine Kinases, Humans, Liposomes, Mice, Mice, Nude, Neovascularization, Pathologic, Ovarian Neoplasms, Phosphatidylcholines, RNA, Small Interfering, Xenograft Model Antitumor Assays
Abstract

PURPOSE: 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).

EXPERIMENTAL DESIGN: 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.

RESULTS: 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.

CONCLUSIONS: Taken together, these findings suggest that FAK siRNA-DOPC plus docetaxel or platinum might be a novel therapeutic approach against ovarian cancer.

DOI10.1158/1078-0432.CCR-06-0021
Alternate JournalClin. Cancer Res.
PubMed ID16914580
PubMed Central IDPMC3144499
Grant List2P50CA083639-06A1 / CA / NCI NIH HHS / United States
CA10929801 / CA / NCI NIH HHS / United States
CA11079301 / CA / NCI NIH HHS / United States
P50 CA083639 / CA / NCI NIH HHS / United States
P50 CA083639-02 / CA / NCI NIH HHS / United States
R01 CA109298 / CA / NCI NIH HHS / United States
R01 CA109298-01A1 / CA / NCI NIH HHS / United States
R01 CA110793 / CA / NCI NIH HHS / United States
R01 CA110793-01 / CA / NCI NIH HHS / United States