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Developmental Biology - Birth Defects
The Story of Thalidomide Continues
The molecular affect of the drug on limb and ear development may rely on a specific protein just identified...
Researchers in Japan and Italy have deepened our understanding of how thalidomide causes developmental abnormalities at the molecular level.
Tokyo Institute of technology (Tokyo Tech) and Tokyo Medical University have unveiled a detailed view of how thalidomide — one of the most notorious drugs ever developed — causes abnormalities in limb and ear development.
These findings may help contribute to a re-emergence of safer, non-teratogenic, thalidomide-derived drugs as a treatment for cancer and inflammatory diseases.
Thalidomide has a reputation as one of the most potent substances to cause birth defects. Originally used in the late 1950s as a treatment for morning sickness, evidence in the early 1960s linked thalidomide to physical abnormalities such as shortened limbs and defective organs, leading to its world wide ban.
Remarkably, based on subsequent findings concentrating on thalidomide's anti-inflammatory properties, it may become repurposed to treat conditions such as leprosy and multiple myeloma (a type of blood cancer).
"The thalidomide tragedy is not an open-and-shut case in medical history, but is ongoing as new thalidomide babies have been born after its re-approval around 2000."
"We now know thalidomide and its derivative drugs are highly effective and associated with few side-effects, except for teratogenic effects on the fetus — unlike many other conventional anti-cancer agents.
"Teratogenicity is still a big hurdle for wider application of these promising drugs."
Yuki Yamaguchi PhD, Biochemist, Tokyo Technology.
To investigate the mechanisms behind thalidomide activity in more detail, Yamaguchi collaborated with Hiroshi Handa of Tokyo Medical University, Luisa Guerrini of Universita degli Studi di Milano, Italy, and others to conduct developmental studies using zebrafish as a model organism. The collaborators set out to explore Guerrini's hunch that the p63 family of proteins might be critically involved.
In 2010, a team led by Handa and Yamaguchi achieved a breakthrough by identifying cereblon as a key protein through which thalidomide initiates its adverse or teratogenic effects. (See Molecular Basis of Brain Dysfunction and Embryo Malformation Associated with Thalidomide.)
Now, the latest study published in Nature Chemical Biology shows that after binding to cereblon, thalidomide causes damage to fins in fish and limbs in humans; as well as to otic vesicles (corresponding to ears) by inducing breakdown of two types of p63 proteins. Specifically, the study suggests that the breakdown of Np63a results in limb defects, while that of TAp63a leads to ear defects, as shown in Figure 1.
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Understanding how cereblon works to mediate the effects of thalidomide could transform the way drugs are developed - moving away from serendipitous discovery and towards rational molecular design. "The change would be like a shift from looking for a needle in a haystack to carving a needle out of bone," Yamaguchi notes.
"It's likely that we will see the development of new thalidomide-based drugs without teratogenic effects in the near future."
Yuki Yamaguchi PhD.
Abstract
Cereblon (CRBN) is a primary target of thalidomide and mediates its multiple pharmacological activities, including teratogenic and antimyeloma activities. CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs. Although a number of CRL4CRBN substrates have recently been identified, the substrate involved in thalidomide teratogenicity is unclear. Here we show that p63 isoforms are thalidomide-dependent CRL4CRBN neosubstrates that are responsible, at least in part, for its teratogenic effects. The p53 family member p63a is associated with multiple developmental processes. Np63a is essential for limb development, while TAp63a is important for cochlea development and hearing. Using a zebrafish model, we demonstrate that thalidomide exerts its teratogenic effects on pectoral fins and otic vesicles by inducing the degradation of Np63a and TAp63a, respectively. These results may contribute to the invention of new thalidomide analogs lacking teratogenic activity.
Authors
Tomoko Asatsuma-Okumura, Hideki Ando, Marco De Simone, Junichi Yamamoto, Tomomi Sato, Nobuyuki Shimizu, Kazuhide Asakawa, Yuki Yamaguchi, Takumi Ito, Luisa Guerrini and Hiroshi Handa.
Acknowledgments
The authors thank M. Manabe, M. Akiyama, S. Shoji and K. Taneda for technical assistance. We also thank A. J. Berk for critical comments on this manuscript. This work was supported by MEXT/JSPS KAKENHI grant numbers 17H06112 (to H.H. and Y.Y.), 15H04288 (to H.A.), 17H04213 (to T.I.), 17K14996 (to J.Y.) and 18H05502 (to T.I.). This work was also supported by MEXT-Supported Program for the Strategic Research Foundation at Private Universities S1411011 (to H.H.) and by PRESTO, JST JPMJPR1531 (to T.I.).
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Oct 21 2019 Fetal Timeline Maternal Timeline News
Manuel Bioque, Spanish victim of the drug thalidomide. CREDIT Carlos Rosillo EL PAIS.
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