Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont.
Am J Respir Cell Mol Biol. 2014 Nov;51(5):595-603. doi: 10.1165/rcmb.2013-0373TR.
Malignant mesothelioma (MM), lung cancers, and asbestosis are hyperproliferative diseases associated with exposures to asbestos. All have a poor prognosis; thus, the need to develop novel and effective therapies is urgent. Vandetanib (Van) (ZD6474, ZACTIMA) is a tyrosine kinase inhibitor that has shown equivocal results in clinical trials for advanced non-small cell lung cancer. However, tyrosine kinase inhibitors alone have shown no significant clinical activity in phase II trials of patients with unresectable MM. Using epithelioid (HMESO) and sarcomatoid (H2373) human MM lines, the efficacy of tumor cell killing and signaling pathways modulated by Van with and without doxorubicin (Dox) was examined. Van alone reduced total cell numbers in HMESO MM and synergistically increased the toxicity of Dox in HMESO and H2373 cells. Most importantly, we identified two novel cell survival/resistance pathways, ERK5 and cyclic AMP response element binding protein (CREB), that were inhibited by Van and Dox. After silencing of either ERK5 or CREB, significant decreases in cell numbers in the Dox-resistant sarcomatoid H2373 line were observed. Results suggest that a plethora of cell signaling pathways associated with cell survival are induced by Dox but inhibited by the addition of Van in MM. Data from our study support the combined efficacy of Van and Dox as a novel approach in the treatment of MM that is further enhanced by blocking ERK5 or CREB signaling cascades.
恶性间皮瘤（MM）、肺癌和石棉沉着症是与石棉暴露相关的增殖性疾病。所有这些疾病的预后都很差；因此，迫切需要开发新的有效疗法。凡德他尼（Van）（ZD6474，ZACTIMA）是一种酪氨酸激酶抑制剂，在晚期非小细胞肺癌的临床试验中结果喜忧参半。然而，在无法切除的 MM 患者的 II 期临床试验中，单独使用酪氨酸激酶抑制剂并没有显示出显著的临床活性。使用上皮样（HMESO）和肉瘤样（H2373）人 MM 系，研究了 Van 及其与多柔比星（Dox）联合应用对肿瘤细胞杀伤和信号通路的调节作用。Van 单独使用可减少 HMESO MM 中的总细胞数，并协同增加 HMESO 和 H2373 细胞中 Dox 的毒性。最重要的是，我们确定了两种新的细胞存活/抵抗途径，ERK5 和环磷酸腺苷反应元件结合蛋白（CREB），它们被 Van 和 Dox 抑制。沉默 ERK5 或 CREB 后，观察到 Dox 耐药肉瘤样 H2373 系的细胞数量显著减少。结果表明，Dox 诱导了大量与细胞存活相关的细胞信号通路，但 MM 中添加 Van 可抑制这些通路。我们的研究数据支持 Van 和 Dox 的联合疗效作为 MM 治疗的一种新方法，通过阻断 ERK5 或 CREB 信号级联进一步增强。
