title: SK-216, an inhibitor of plasminogen activator inhibitor-1, limits tumor progression and angiogenesis.
abstract: 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.
authors.affiliation: Corresponding Author: Noboru Hattori, Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. nhattori@hiroshima-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masuda
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
authors.forename: Tadashi
authors.initials: T
authors.lastname: Senoo
authors.forename: Shin
authors.initials: S
authors.lastname: Akita
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Haruta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murai
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001583:Benzoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D001583:Benzoxazoles; D003998:Dicarboxylic Acids; D017395:Plasminogen Activator Inhibitor 1; C000589255:SK-216