Adeno-associated virus-mediated delivery of kringle 5 of human plasminogen inhibits orthotopic growth of ovarian cancer

Abstract

Kringle 5 (K5) of human plasminogen is a potent angiogenesis inhibitor. In this study, we investigated the effects of recombinant adeno-associated virus (AAV)-mediated delivery of K5 in mouse models of human ovarian cancer. A single intramuscular injection of AAV-K5 resulted in sustained expression of K5 reaching a maximum serum level of 800 ng ml À1. Gene therapy inhibited both vascular endothelial growth factor (VEGF)-induced and tumor cell-induced angiogenesis in matrigel plug assays. Furthermore, a single injection of AAV-K5 significantly inhibited both subcutaneous and intraperitoneal growth of human ovarian cancer cells. Immunofluorescence studies of residual tumors surgically resected from the treated animals showed reduced tumor burden, which correlated with the inhibition of tumor neovascularization. In addition, AAV-K5 gene therapy differentially affected the nascent vessels more than mature vasculature and induced apoptotic death of tumor cells. These data show that AAV-K5 can be effectively used to inhibit ovarian cancer.

Efficient Inhibition of Ovarian Cancer by Truncation Mutant of FILIP1L Gene Delivered by Novel Biodegradable Cationic Heparin-Polyethyleneimine Nanogels

“…Over the last decade, many functional genes have been reported to effectively inhibit ovarian cancer in vitro and in vivo (Malek et al, 2008;Nguyen et al, 2010), but the absence of efficient and safe gene delivery technologies is a major obstacle to the clinical use of these gene treatments. Currently, many delivery systems have been applied in gene transfer; these are generally classified as nonviral and viral vectors.…”

Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells

“…By now, many cancer gene therapy studies aim at various targets to correct their aberrant expression in tumors, such as inhibition of over-expressed oncogenes, multidrug resistant genes, anti-apoptotic genes, or re-expression of extrinsic normal tumor suppressor genes, introducing tumor suicide genes, anti-angiogenesis genes, apoptosis-inducing genes, immunostimulating genes or in combinations to suppress tumor growth and metastasis, induce apoptosis or mitigating drug resistance, etc. Recently reported works include blocking of a serine/threonine protein kinase Akt (also known as Protein Kinase B, PKB) which plays a key role in multiple cellular processes including glucose metabolism, cell proliferation and cell migration [21]; knock-down of a cell cycle inhibitor BMI-1 (B lymphoma Mo-MLV insertion region 1 homolog) which could enhance drug resistance in B-cell lymphoma cells through the regulation of survivin, a gene often overexpressed in various human cancers to function as an oncogene [22]; silencing Cathepsin B and uPAR (Urokinase type plasminogen activator receptor) overexpressed and involved in tumor angiogenesis, which is vital for tumor progression, migration [23]; suppressing a novel prenylated tyrosine phosphatase PRL-3 which is important in cancer metastasis [24]; inhibiting livin, a new inhibitor of apoptosis protein family [25]; or enhancing the expression of gap junction alpha-1 protein Cx43, an inhibitor of malignant phenotype [26]; increasing the level of DLC1, a tumor growth suppressor gene, frequently silenced in multiple common tumors [27]; strengthening Kringle 5 of human plasminogen, a potent angiogenesis inhibitor [28]; boosting maspin (mammary serine protease inhibitor) functioning to suppress angiogenesis, invasion and metastasis of cancer cells, which could reverse resistance to chemotherapeutic drugs [29]. However, one important issue is that targeting one gene in different tumor cells may result in different antitumor efficacies, or an effective antitumor effect was only limited to some types of tumor, not applicable for other types of tumors, because the alterations of the genes responsible in different tumors are variable.…”

Efficient inhibition of ovarian cancer by recombinant CXC chemokine ligand 10 delivered by novel biodegradable cationic heparin-polyethyleneimine nanogels

“…Over the last decade, many other functional genes have been reported to effectively inhibit ovarian cancer in vitro and in vivo (36,37). However, the lack of safe and efficient gene delivery approach is a major obstacle to the applications of gene treatments in clinical practice.…”