title: Administration of PLGA nanoparticles carrying shRNA against focal adhesion kinase and CD44 results in enhanced antitumor effects against ovarian cancer.
abstract: The two membrane-bound proteins, focal adhesion kinase (FAK) and CD44, are involved in processes critical to cancer progression. FAK has an active role in angiogenesis, cell proliferation and cell apoptosis, whereas the heavily glycosylated CD44 has been implicated in cancer metastasis. Here, using short hairpin RNA (shRNA) against FAK and CD44, we demonstrate that simultaneous knockdown of both these genes inhibits cancer growth more efficiently than knockdown of either gene individually. Plasmids targeting these genes or non-relative control sequences were constructed and delivered to ovarian cancer targets by biodegradable poly D,L-lactide-co-glycolide acid nanoparticles (PLGANPs). Nude mice were utilized in an intraperitoneal model of ovarian carcinomatosis to assess antitumor efficacy in vivo. Single gene knockdown resulted in significantly smaller tumors than those observed in the empty-vector control (P's<0.001). More importantly, knockdown of both genes resulted in tumors smaller than both the empty-vector group (P<0.0001) and the single gene knockdown groups (P's<0.001). Knockdown of both FAK and CD44 resulted in tumors with inhibited angiogenesis, reduced proliferation and increased apoptosis as compared with controls (P's<0.001) and single knockdown groups (P's<0.05). These results indicate that dual knockdown of FAK and CD44 in the tumors of patients with ovarian cancer may have an enhanced therapeutic effect, and point toward a mechanism involving the inhibition of angiogenesis, cellular proliferation and the induction of apoptosis.
authors.affiliation: Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Zou
authors.forename: X
authors.initials: X
authors.lastname: Song
authors.forename: T
authors.initials: T
authors.lastname: Yi
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Deng
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Bai
authors.forename: Q
authors.initials: Q
authors.lastname: Zhong
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
authors.forename: X
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000628:therapy; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D047368:Tumor Burden
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D051416:Focal Adhesion Protein-Tyrosine Kinases