我们运用从老药中发现新适应症的策略筛选发现一个治疗血小板增多症的老药：磷酸二酯酶ⅢA（PDE3A）抑制剂Anagrelide（ANA）有选择性抑制肿瘤细胞增殖和诱导肿瘤细胞凋亡的抗肿瘤新功能。该项目围绕ANA的抗肿瘤新活性，对ANA抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、以及其细胞选择性的分子机理分别展开深入系统的研究。首先是明确PDE3A及其调控的cAMP/CREB信号通路在ANA抑制肿瘤细胞增殖和诱导凋亡中的功能，其次是发现介导ANA抑瘤活性的新蛋白和新机制，最终是阐明ANA的细胞选择性机理，为临床运用ANA进行肿瘤治疗提供依据、诊断方法和用药指导，同时也将揭示新的抗肿瘤药物靶点和新的调控肿瘤细胞生长的机理。

Using an “old drug new indication” strategy, we have identified an anti-essential thrombocytosis drug and a phosphodieaterase 3A (PDE3A) inhibitor Anagrelide (ANA) that inhibited cell proliferation or induced apoptosis of selected cancer cells. The present proposal is to investigate the molecular mechanisms of ANA in inhibiting cell proliferation and in inducing apoptosis. It also investigate the mechanisms underlying the selectivity of ANA. The goal is to understand the role of PDE3A and its cAMP/CREB signaling pathway and to identify new proteins and mechanisms in mediating the ANA-induced cell growth arrest and apoptosis. The results of this study will provide the basis and guidance for using ANA as an anti-cancer drug. It may also reveal novel anti-cancer drug targets and mechanisms regulating cancer cell growth.