Cancers of the urinary bladder result in aggressive and highly angiogenic
tumors for which standard treatments have only limited success. Patients with advanced disease have a 5-year survival rate of less than 20%, and no new
anticancer agent has been successfully introduced into the clinic armamentarium for the treatment of
bladder cancer in more than 20 years. Investigations have identified
plasminogen activator inhibitor-1 (PAI-1), a
serine protease inhibitor, as being highly expressed in several
malignancies, including
bladder cancer, in which high expression is associated with a poor prognosis. In this study, we evaluated
PAI-1 as a potential therapeutic target for
bladder cancer.
PAI-1 expression was manipulated in a panel of cell lines and functional inhibition was achieved using the small molecule
tiplaxtinin. Reduction or inhibition of
PAI-1 resulted in the reduction of cellular proliferation, cell adhesion, and colony formation, and the induction of apoptosis and anoikis in vitro. Treatment of T24 xenografts with
tiplaxtinin resulted in inhibition of angiogenesis and induction of apoptosis, leading to a significant reduction in
tumor growth. Similar results were obtained through evaluation of the human
cervical cancer HeLa cell line, showing that PAI-1-mediated effects are not restricted to
tumor cells of bladder origin. Collectively, these data show that targeting
PAI-1 may be beneficial and support the notion that novel drugs such as
tiplaxtinin could be investigated as
anticancer agents.