ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC.

Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

“…We first examined the effect of apoA-I overexpression on overall survival in a mouse (C57BL/ 6J) model of ovarian cancer (21)(22)(23). The survival studies were performed in wild-type C57BL/6J mice and hApoA-I/Tg mice on a C57BL/6J background.…”

“…LPA induces migration and invasion in both mouse and human epithelial ovarian cancer cells (20). Recent studies demonstrate that the mouse epithelial cancer cell line named ID8 is an ideal model system to test the effects of LPA and therapeutic agents of ovarian cancer in immunocompetent mouse models (21,22).…”

ABT-898 Induces Tumor Regression and Prolongs Survival in a Mouse Model of Epithelial Ovarian Cancer

“…Although several studies have targeted the VEGF family in ovarian cancer (15)(16)(17)(18), another effective approach for the treatment of various cancers are peptides derived from the TSR antiangiogenic domain of TSP-1 (19). Numerous studies have shown the antiangiogenic and antitumor effects of 3TSR (20)(21)(22) and ABT-510 (11,23,24) and have shown safety and efficacy in animal and human studies (12,13,25,26). We have previously evaluated ABT-510 in the treatment of EOC and reported decreased tumor burden as well as an increase in the uptake of the chemotherapy drugs cisplatin and paclitaxel through vascular normalization (8).…”

“…The type I repeat region (TSR) of TSP-1 binds and activates the receptor CD36, which mediates the antiangiogenic effects of TSP-1 such as increased apoptosis and impaired migration and chemotaxis (9,10). We have shown in a mouse model of EOC that this region is capable of decreasing the size of ovarian tumors and inhibiting the formation of peritoneal lesions and ascites fluid (8,11). A second generation TSP-1 mimetic peptide, ABT-898, has been generated that has enhanced stability, an increased half-life of 4 to 5 hours, and has minimal side effects or toxicities (12,13).…”

Molecular Basis for the Regulation of Angiogenesis by Thrombospondin-1 and -2

“…All of these studies have, however, established an acceptable safety profile of the drug. Furthermore, experimental work has supported the role of ABT-510 as an adjuvant chemotherapy, which can potentiate the antitumor effects of more traditional, cytotoxic chemotherapy, including in ovarian cancer (Greenaway et al 2009;Campbell et al 2010). It is possible that ABT-510 specifically or other TSP mimetics will prove efficacious as an adjuvant chemotherapy, perhaps improving clinical outcomes and permitting lower exposure to more traditional cytotoxic chemotherapeutics.…”