Targeting plasminogen activator inhibitor-1 inhibits angiogenesis and tumor growth in a human cancer xenograft model.
Targeting plasminogen activator inhibitor-1 inhibits angiogenesis and tumor growth in a human cancer xenograft model.
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DOI：
10.1158/1535-7163.mct-13-0500
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发表时间：
2013-12
影响因子：
5.7
通讯作者：
Rosser CJ
中科院分区：
文献类型：
--
作者：
Gomes-Giacoia E;Miyake M;Goodison S;Rosser CJ
膀胱癌导致侵袭性和高度血管生成的肿瘤，标准治疗仅具有有限的成功。晚期膀胱癌患者的5年生存率低于20%，20多年来没有新的抗癌药物被成功引入临床治疗膀胱癌。研究已经确定纤溶酶原激活物抑制剂-1（派-1），一种丝氨酸蛋白酶抑制剂，在包括膀胱癌在内的几种恶性肿瘤中高度表达，其中高表达与不良预后相关。在这项研究中，我们评估派-1作为膀胱癌的潜在治疗靶点。在一组细胞系中操纵派-1表达，并使用小分子替普拉替宁实现功能抑制。派-1的减少或抑制导致细胞增殖、细胞粘附和集落形成的减少，并诱导细胞凋亡和失巢凋亡。用替普拉替宁处理T24异种移植物导致血管生成的抑制和细胞凋亡的诱导，从而导致肿瘤生长的显著减少。通过对人宫颈癌HeLa细胞系的评估获得了类似的结果，表明派-1介导的作用不限于膀胱来源的肿瘤细胞。总的来说，这些数据表明，靶向派-1可能是有益的，并支持新的药物，如tiplaxtinin可以作为抗癌药物进行研究的概念。
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.