Cilengitide Inhibits Attachment and Invasion of Malignant Pleural Mesothelioma Cells through Antagonism of Integrins αvβ3 and αvβ5

Malignant pleural mesothelioma (MPM) is an almost invariably fatal, asbestos-related malignancy arising from the mesothelial membrane lining the thoracic cavities. Despite some improvements in treatment, therapy is not considered curative and median survival following diagnosis is less than 1 year. Although still classed as a rare cancer, the incidence of MPM is increasing, and the limited progress in treating the disease makes the identification of new therapies a priority. As there is evidence for expression of the integrins αvβ3 and αvβ5 in MPM, there is a rationale for investigating the effects on MPM of cilengitide, a synthetic peptide inhibitor of integrin αv heterodimer with high specificity for αvβ3 and αvβ5. In mesothelial cells (MC) and 7 MPM cell lines, growth inhibition by cilengitide was associated with the expression level of its target integrins. Furthermore, cilengitide caused cell detachment and subsequent death of anoikis-sensitive cells. It also suppressed invasion of MPM cells in monolayer and three-dimensional cultures. Gene knockdown experiments indicated that these effects of cilengitide were, at least partly, due to antagonism of αvβ3 and αvβ5.

恶性胸膜间皮瘤（Malignant pleural mesothelioma, MPM）是一种几乎必然致命的、与石棉暴露相关的恶性肿瘤，起源于胸膜腔内衬的间皮膜。尽管治疗手段已取得一定进展，但目前仍无法实现根治，确诊后的中位生存期不足1年。尽管MPM仍被归类为罕见癌症，但其发病率正持续上升，加之该疾病的治疗进展有限，因此研发新型治疗方案已成为当务之急。已有研究证实，MPM细胞可表达整合素αvβ3与αvβ5，这为探究西仑吉肽（cilengitide）对MPM的作用提供了理论依据——西仑吉肽是一种对αvβ3和αvβ5具有高特异性的整合素αv异二聚体合成肽类抑制剂。在间皮细胞（mesothelial cells, MC）及7株MPM细胞系中，西仑吉肽介导的生长抑制效应与其靶整合素的表达水平显著相关。此外，西仑吉肽可诱导细胞脱附，并引发失巢凋亡敏感细胞的死亡；同时其还能抑制单层及三维培养体系中MPM细胞的侵袭能力。基因敲低实验表明，西仑吉肽的上述效应至少部分是通过拮抗αvβ3和αvβ5整合素实现的。