Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Insights into side effects of thalidomide using magnetic nanoparticles

06.03.2012
Tokyo Tech’s Hiroshi Handa and colleagues have identified a key protein— cereblon —involved in the development of birth defects associated with thalidomide using unique sub-micrometer functionalized magnetic nanobeads. The discovery opens up possibilities for the development of safer drugs for the treatment of multiple myeloma and leprosy.
Hiroshi Hanada describes his research on magnetic particles for biomedicine in a video interview in the latest Feb 2012 issue of Tokyo Tech’s on line newsletter the Tokyo Tech Bulletin: http://www.titech.ac.jp/bulletin/

Details about Hiroshi Handa’s report on the ‘Identification of a Primary Target of Thalidomide Teratogenicity’ published in Science 327, 1345 (2010).

Thalidomide was prescribed as a sedative for pregnant women to treat morning sickness in the late 1950s. It was removed from the market in the early 1960s, when its use was linked to birth defects including shortened or absent limbs, as well as ear, cardiac and gastrointestinal malformations. However, within a few years the powerful pain relief properties of thalidomide for leprosy patients suggested that the drug may yet have medical benefits. In the 1990s it was also proven to be effective in the treatment of the cancer multiple myeloma.

It is still little understood how use of thalidomide leads to the development of birth defects, and tight restrictions are maintained over administration of the drug to treat leprosy and cancer. Insights into the mechanism behind the toxic effects of thalidomide on pregnant women could help to find ways to avoid these side effects and release the potential of the drug as a powerful medical aid.

Researchers at Tokyo Tech have recently reported the development of high-performance affinity beads – magnetic beads 200 nm in diameter that can be attached to drugs and other compounds, allowing one-step affinity purification of drug targets and an insight into how the drugs act [2]. As Hiroshi Handa and his colleagues explain, “Currently, most commercially available drugs and physiologically active substances have been brought to market without knowledge of factors interacting with the drugs and the substances.” Handa have now applied the beads to unravelling the mystery behind the birth defects caused by thalidomide [1].

The researchers used ferrite glycidyl methacrylate beads for purity affiliation of thalidomide, and identified cereblon as a protein that binds directly with the drug. The researchers then performed in vivo experiments in zebrafish, which were recently shown to be affected by thalidomide during embryonic development and have the useful attribute of a transparent embryo so that the progress of development can be conveniently monitored. Knockdown of genes of interest is also easily implemented in zebrafish. Thalidomide treatment was found to noticeably affect the development of the pectoral fins and otic vesicles, which it is suggested, share common molecular pathways with that of developing limbs and ears in tetrapods.
Zebrafish have a gene that is orthologously similar to cereblon in humans. The researchers investigated the development of embryos in which this gene was knocked down and similar defects were observed as for embryos treated with thalidomide. Co-injection of messenger RNA for the cereblon-orthologous gene was found to rescue these defects. The results suggest a potential means to reverse the developmental problems caused by thalidomide treatment.

The researchers then investigated the role of cereblon in chicks, which are well-established model organisms for studying thalidomide-induced birth defects. Experiments on chicks further supported the conclusion that cereblon is a direct target in thalidomide-induced birth defects.

Thalidomide treatment or down regulation of the CRBN complex causes developmental defects in zebrafish.

The action of thalidomide is complex and it is associated with a number of other mechanisms that may also cause problems in fetal development, including oxidative stress and antiangiogenic activity. However, as Handa and his colleagues explain, “identification of thalidomide’s direct target may allow rational design of more effective thalidomide derivatives without teratogenic activity”. The work holds promise for a role of thalidomide in medical treatment that is not blighted by the side effects observed in the past.

References:
[1] T. Ito, H. Ando, T. Suzuki, T. Ogura, K. Hotta,Y. Imamura, Y. Yamaguchi & H. Handa. “Identification of a Primary Target of Thalidomide Teratogenicity,” Science 327, 1345 (2010).

[2]S. Sakamoto, Y. Kabe, M. Hatakeyama, Y. Yamaguchi, & H. Handa. “Development and application of high-performance affinity beads: Toward chemical biology and drug discovery,” The Chemical Record 9, 66-85 (2009).

Contact:

Hidekazu Ueda and Yukiko Tokida
Center for Public Information
Tokyo Institute of Technology
2-12-1, Ookayama, Meguro-ku, Tokyo 152-8550, Japan
E-mail: kouhou@jim.titech.ac.jp

Tel: +81-3-5734-2975
Fax: +81-3-5734-3661

About Tokyo Institute of Technology

As one of Japan’s top universities, Tokyo Institute of Technology seeks to contribute to civilization, peace and prosperity in the world, and aims at developing global human capabilities par excellence through pioneering research and education in science and technology, including industrial and social management. To achieve this mission, we have an eye on educating highly moral students to acquire not only scientific expertise but also expertise in the liberal arts, and a balanced knowledge of the social sciences and humanities, all while researching deeply from basics to practice with academic mastery. Through these activities, we wish to contribute to global sustainability of the natural world and the support of human life.

Expression of a drug binding–deficient form of CRBN suppresses thalidomide-induced limb malformations in chicks. A, anterior; Pos, posterior; Pro, proximal; D, distal; Thal, thalidomide; FH-CRBN, epitope–tagged CRBN. Scale bar is 1 mm.

Adarsh Sandhu | ResearchSEA
Further information:
http://www.titech.ac.jp/english/
http://www.researchsea.com

More articles from Life Sciences:

nachricht Quality control in immune communication: Chaperones detect immature signaling molecules in the immune system
20.09.2019 | Technische Universität München

nachricht Moderately Common Plants Show Highest Relative Losses
20.09.2019 | Universität Rostock

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: 'Nanochains' could increase battery capacity, cut charging time

How long the battery of your phone or computer lasts depends on how many lithium ions can be stored in the battery's negative electrode material. If the battery runs out of these ions, it can't generate an electrical current to run a device and ultimately fails.

Materials with a higher lithium ion storage capacity are either too heavy or the wrong shape to replace graphite, the electrode material currently used in...

Im Focus: Stevens team closes in on 'holy grail' of room temperature quantum computing chips

Photons interact on chip-based system with unprecedented efficiency

To process information, photons must interact. However, these tiny packets of light want nothing to do with each other, each passing by without altering the...

Im Focus: Happy hour for time-resolved crystallography

Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Hamburg and the European Molecular Biology Laboratory (EMBL) outstation in the city have developed a new method to watch biomolecules at work. This method dramatically simplifies starting enzymatic reactions by mixing a cocktail of small amounts of liquids with protein crystals. Determination of the protein structures at different times after mixing can be assembled into a time-lapse sequence that shows the molecular foundations of biology.

The functions of biomolecules are determined by their motions and structural changes. Yet it is a formidable challenge to understand these dynamic motions.

Im Focus: Modular OLED light strips

At the International Symposium on Automotive Lighting 2019 (ISAL) in Darmstadt from September 23 to 25, 2019, the Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, a provider of research and development services in the field of organic electronics, will present OLED light strips of any length with additional functionalities for the first time at booth no. 37.

Almost everyone is familiar with light strips for interior design. LED strips are available by the metre in DIY stores around the corner and are just as often...

Im Focus: Tomorrow´s coolants of choice

Scientists assess the potential of magnetic-cooling materials

Later during this century, around 2060, a paradigm shift in global energy consumption is expected: we will spend more energy for cooling than for heating....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Optical Technologies: International Symposium „Future Optics“ in Hannover

19.09.2019 | Event News

Society 5.0: putting humans at the heart of digitalisation

10.09.2019 | Event News

Interspeech 2019 conference: Alexa and Siri in Graz

04.09.2019 | Event News

 
Latest News

Quality control in immune communication: Chaperones detect immature signaling molecules in the immune system

20.09.2019 | Life Sciences

Moderately Common Plants Show Highest Relative Losses

20.09.2019 | Life Sciences

The Fluid Fingerprint of Hurricanes

20.09.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>