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. Mol Cancer Ther; 12(11); 2378-88. Ó2013 AACR.

Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma

“…In each mouse model of MPM using EHMES-10 cells or MSTO-211H cells, the antitumor effect of cisplatin was augmented by combining it with SK-216. In vitro, inhibition of PAI-1 by SK-216 suppressed migration and tube formation of HUVECs induced by bFGF, PDGF-BB, and HGF, as well as by VEGF, as reported previously (31).…”

“…6C and E, however, SK-216 was found to inhibit both migration and tube formation of HUVECs induced by bFGF, PDGF-BB, or HGF in a dose-dependent manner. A similar inhibitory effect of SK-216 on migration and tube formation of HUVECs was demonstrated in our previous study using VEGF as the inducer (31).…”

“…Recently, we demonstrated that inhibition of PAI-1 by a specific inhibitor of PAI-1, SK-216, limited tumor angiogenesis in vivo and migration and tube formation of human umbilical vein endothelial cells (HUVEC) induced by VEGF in vitro (31).…”

“…Because the antiangiogenic activity of SK-216 was demonstrated in vivo irrespective of the primary angiogenic factor produced by the tumor, we assessed whether SK-216 affected proliferation, migration, and tube formation of endothelial cells induced by bFGF, PDGF-BB, and HGF, as in our previous study that used induction by VEGF (31). The proliferation assay showed that SK-216 did not affect the proliferation rate of HUVECs in the copresence of each angiogenic factor in culture (Fig.…”

Plasma Levels of Plasminogen Activator Inhibitor Type 1 and Vitronectin in Children With Cancer

“…21 Masuda et al suggested that regardless of the levels of PAI-1 in the tumor, the systemic administration of SK-216, a specific PAI-1 inhibitor, exerts an antitumor effect through its interaction with host PAI-1 in PAI-1-secreting Lewis lung carcinoma or PAI-1 nonsecreting B16 melanoma cells. 22 It was reported that serine protease uPA and matrix metalloprotease (MMP) 2/MMP-9) play an important role in glioblastoma multiform growth in rat model. 23 Halamkova et al examined the expression of uPA, uPAR, PAI-1, and PAI-2 in tumor tissue and studied the plasma levels of PAI-1 before and after the initiation of therapy in patients with colorectal carcinoma in relationship with the grade of tumor and the treatment response.…”