Department of Pneumology, Clinic III for Internal Medicine, University of Cologne, D-50924 Cologne, Germany.
Curr Mol Pharmacol. 2011 Jan;4(1):26-61. doi: 10.2174/1874467211104010026.
Thalidomide is a powerful treatment for inflammatory and cancer-based diseases. However, its clinical use remains limited due to its teratogenic properties, which primarily affect limb development. A prerequisite for overcoming these limitations is to understand the cellular and molecular mechanisms underlying thalidomide teratogenicity, which involve induction of oxidative stress, suppression of ubiquitin-mediated protein degradation and disruption of angiogenesis. Here, we discuss the hypothesis that thalidomide-induced limb teratogenicity is primarily based on the generation of nuclear oxidative stress with subsequent induction of transient apoptosis in the outgrowing limb bud. To this end, we establish a model of the signaling network regulating cell proliferation, survival and endogenous apoptosis-induction required for correct limb outgrowth and patterning. We then summarize data showing how thalidomide interferes with this signaling network: thalidomide inhibits the activity of the redox-sensitive transcription factor NF-κB, shifts the balance of fibroblast growth factors and bone morphogenetic proteins (Bmps) towards pro-apoptotic Bmps, and suppresses Wnt/β-catenin- and Akt-dependent survival signaling in the limb bud. Consequently, prechondrogenic precursor cells that determine skeletal elements are eliminated leading to the development of truncated limbs. We further discuss the involvement of thalidomide effects on ubiquitin-mediated protein degradation and angiogenesis in the induction of apoptosis in the limb bud. Finally, we discuss the paradox that the embryonic molecular pathology induced by thalidomide suggests this drug as a candidate for therapeutic application in idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease characterized by downregulation of Bmp signaling, increased Wnt and Akt activity, and apoptosis resistance.
沙利度胺是一种治疗炎症和癌症疾病的有效药物。然而，由于其致畸特性，主要影响四肢发育，其临床应用仍然受到限制。克服这些限制的前提是了解沙利度胺致畸的细胞和分子机制，这涉及诱导氧化应激、抑制泛素介导的蛋白质降解和破坏血管生成。在这里，我们讨论了这样一种假设，即沙利度胺诱导的肢体畸形主要基于核氧化应激的产生，随后在外生肢体芽中诱导瞬时细胞凋亡。为此，我们建立了一个调节细胞增殖、存活和内源性凋亡诱导的信号网络模型，这些都是正确的肢体生长和模式形成所必需的。然后，我们总结了表明沙利度胺如何干扰这个信号网络的数据：沙利度胺抑制了氧化还原敏感转录因子 NF-κB 的活性，使成纤维细胞生长因子和骨形态发生蛋白 (Bmps) 的平衡向促凋亡的 Bmps 倾斜，并抑制了肢体芽中 Wnt/β-catenin 和 Akt 依赖性存活信号。因此，决定骨骼元素的预成软骨前体细胞被消除，导致肢体缩短。我们进一步讨论了沙利度胺对泛素介导的蛋白质降解和血管生成的影响在诱导肢体芽细胞凋亡中的作用。最后，我们讨论了一个悖论，即沙利度胺诱导的胚胎分子病理学表明，这种药物可能是特发性肺纤维化 (IPF) 的治疗候选药物，IPF 是一种慢性和致命的肺部疾病，其特征是 Bmp 信号下调、Wnt 和 Akt 活性增加以及凋亡抵抗。
