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.

Immunomodulatory drugs and their therapeutic effect in hematological malignancies through cereblon

“…Ito, et al [73][74][75][76] developed a new affinity bead technology for isolating ligand-binding proteins. Polymer-coated beads were constructed that allow single-step purification of ligand target molecules.…”

“…The zebrafish was adopted as a model animal for in vivo study of thalidomide teratogenicity [73][74][75][76]. Zebrafish have a protein zCrbn, which is 70% homologous to human CRBN and possesses thalidomide binding activity.…”

Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature

“…Antiangiogenic compounds have been associated with defective luteogenesis, reproductive dysfunction, pregnancy loss, and teratogenesis (41)(42)(43). Previous studies have reported TEM1 expression in several tissues of the mouse embryo (22,44).…”

Toxicity Testing in the 21st Century: Challenges and Perspectives

“…While toxicity testing of chemicals aims to identify and manage hazards to human health and the environment following intended or accidental exposure, pharmaceutical toxicity testing forms a critical part of the risk-benefit assessment which balances the intended beneficial effects on the patient health against observed toxicities and potential adverse effects. The importance of nonclinical toxicity testing and adequate data interpretation in ensuring human safety is underscored by the thalidomide calamity in the early 1960's where world-wide approximately 10,000 children were born with limb malformations [1][2][3]. A more recent incident in 2006 involved TGN1412 [4,5].…”