Targeting plasminogen activator inhibitor-1 inhibits angiogenesis and tumor growth in a human cancer xenograft model.
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.
Corresponding Author: Charles J. Rosser, Cancer Research Institute, MD Anderson Cancer Center, 6900 Lake Nona Boulevard, Orlando, FL 32827. deacdoc@aol.com.
Evan
E
Gomes-Giacoia
Makito
M
Miyake
Steve
S
Goodison
Charles J
CJ
Rosser
D000818:Animals; D023102:Anoikis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin