SK-216, an inhibitor of plasminogen activator inhibitor-1, limits tumor progression and angiogenesis

• Published in: Molecular cancer therapeutics 2013-11, Vol.12 (11), p.2378-2388
• Main Authors: Masuda, Takeshi, Hattori, Noboru, Senoo, Tadashi, Akita, Shin, Ishikawa, Nobuhisa, Fujitaka, Kazunori, Haruta, Yoshinori, Murai, Hiroshi, Kohno, Nobuoki
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Animals; Benzoxazoles - administration & dosage; Benzoxazoles - pharmacology; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - metabolism; Carcinoma, Lewis Lung - pathology; Cell Line, Tumor; Dicarboxylic Acids - administration & dosage; Dicarboxylic Acids - pharmacology; Disease Progression; Gene Knockdown Techniques; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms - secondary; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Plasminogen Activator Inhibitor 1 - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-13-0041

Plasminogen activator inhibitor-1 (PAI-1), which can be produced by host and tumor cells in the tumor microenvironment, is intimately involved in tumor progression. In the present study, to pursue the possibility that PAI-1 could be a therapeutic target in the management of malignancy, SK-216, a specific PAI-1 inhibitor, was orally administered to wild-type mice that were subcutaneously implanted or intravenously injected with either PAI-1-secreting Lewis lung carcinoma (LLC) or PAI-1-nonsecreting B16 melanoma cells. The systemic administration of SK-216 was found to reduce the size of subcutaneous tumors and the extent of metastases, regardless of PAI-1 secretion levels from the tumor cells. SK-216 also reduced the extent of angiogenesis in the tumors and inhibited VEGF-induced migration and tube formation by human umbilical vein endothelial cells in vitro. Then, to determine whether host or tumor PAI-1 was more crucial in tumor progression and angiogenesis, PAI-1-deficient or wild-type mice were subcutaneously implanted or intravenously injected with LLC or PAI-1 knockdown LLC cells. Tumor progression was shown to be controlled by the presence of host PAI-1 and not affected by the PAI-1 levels in the tumors. Similarly, host PAI-1 played a more crucial role in tumor angiogenesis than did tumor PAI-1. These observations suggest that regardless of the PAI-1 levels in the tumor, the systemic administration of SK-216 exerts an antitumor effect through its interaction with host PAI-1. This antitumor effect might be mediated by the antiangiogenic properties of SK-216.