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Abstract
Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.
Highlights
Many gene expression changes result from thalidomide exposure, and seem linked to the vasculature and the cytoskeleton
Tubulin has been shown to bind a byproduct of thalidomide, which could explain the drug’s anti-angiogenic, antiproliferative and anti-migratory actions
Several molecules have been found to protect against thalidomideinduced damage in the embryo, including PBN, Nitric Oxide, Prostaglandin H Synthase and aspirin (Parman et al., 1999; Majumder et al., 2009; Lee et al., 2011; Arlen and Wells, 1996)
Summary
Thalidomide was marketed as a nonaddictive, nonbarbiturate sedative that would be nonlethal if overdoses occurred (unlike barbiturates; Fig. 1B). The possible loss of blood vessels that could cause stress on cells resulting in cell death locally, and the evidence of the formation of thalidomide-induced ROS in vivo can prevent/reduce thalidomide induced damage (Parman et al, 1999; Hansen et al, 2002; Hansen and Harris, 2013; Knobloch et al, 2007; Lee et al, 2011), suggest that both mechanisms together could explain much of the damage and range of damage seen in thalidomide embryopathy. Several studies have demonstrated that Fgf signaling is reduced or lost in developing chicken and rabbit limbs, and zebrafish fins following thalidomide exposure (Hansen et al, 2002; Ito et al, 2010; Knobloch et al, 2011) It is unknown if regulation of Fgf is directly or indirectly dependent on Cereblon expression. Many of these gene expression profile changes are in vascular-related and cytoskeletal-related genes
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