Teratogenic effects of thalidomide: molecular mechanisms

Abstract

Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.

Fig. 1

Schematic model of the oxidative stress hypothesis. Thalidomide induces ROS, and oxidative stress upregulates expression of Bmps through aberrant NF-κB activity. This alteration results in blocking Fgf (Fgf8/Fgf10), Akt, and Wnt pathways known to be important for cell survival and proliferation [4, 22, 36, 46, 47, 51]

Fig. 2

Schematic model of the anti-angiogenesis hypothesis. Anti-angiogenesis induced by thalidomide leads to cell death and downregulation of growth factors including Fgf8/Fgf10. Disruption of growth factor signaling pathways is also likely to be involved in cell death. The sequence of events results in mesenchymal loss and in turn limb deformities [5, 24]

Fig. 3

Identification of a direct target of thalidomide. a Structure of thalidomide (thal)-immobilized FG beads. The carboxy derivative of thalidomide (FR259625) is attached covalently to the amino-group of FG beads. GMA Glycidyl methacrylate. b Thalidomide-binding proteins. CRBN and DDB1 were affinity purified from human cell extracts using thal-immobilized FG beads. No other proteins were detected. Bound proteins were visualized by silver staining. DDB1 indirectly interacts with thalidomide by binding to CRBN [25]

Fig. 4

Schematic model of the molecular mechanisms of thalidomide teratogenicity from a CRBN-centric perspective. Thalidomide binds directly to CRBN and inhibits its E3 ubiquitin ligase activity. This inhibition results in aberrant accumulation of substrates (unknown), which in turn causes developmental defects such as limb deformities, in part through downregulation of Fgfs (Fgf8/Fgf10) [25]. We speculate that the accumulation of substrates might cause oxidative stress and induce anti-angiogenic responses, but the idea has not been experimentally proven