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Tuesday, 14 July, 2015

Light-gated control of cell division

LMU chemists have developed photoresponsive derivatives of an antimitotic drug, which permit light-dependent control of cell division. The new agents could provide the basis for precisely targeted tumor therapies, free of side-effects.

 

In cells incubated with Photostatins in the dark (upper left, OFF), microtubules (green) and cell nuclei (blue) are clearly unaffected. However, exposure to blue light (lower right, ON) leads to disintegration of the microtubules, which results in breakdown of the nuclei and ultimately in cell death. Source: Dirk Trauner/LMU

The cells of higher organisms possess three dynamically modifiable systems of protein filaments, collectively referred to as the cytoskeleton, whose elements play crucial roles in fundamental cellular processes. One of these systems consists of fibrous polymers called microtubules, which are in turn made up of globular subunits called tubulins. As well as serving as highways for intracellular transport, microtubule assemblies form the spindle apparatus that is responsible for the ordered segregation of chromosomes to the daughter cells during cell division (mitosis). Hence, compounds that bind specifically to microtubules provide vital tools for research both on cell reorganization and cargo trafficking, as well as the regulation of mitosis and the pattern of embryonic development. Such agents also find application as inhibitors of the abnormal proliferation that characterizes tumor cells, although they have serious drawbacks, in that they also kill healthy cells in specialized tissues that also need to divide quickly (bone marrow, gastrointestinal tract, etc). However, research led by Professor Dirk Trauner and Dr. Oliver Thorn-Seshold at LMU‘s Department of Chemistry has developed an innovative chemical strategy which allows their inhibitory effect to be localized to a selected tissue site, and so should avoid the collateral damage that such drugs normally cause. “We have incorporated a light-sensitive molecular switch into a known inhibitor of microtubule polymerization, so that the agent only becomes active when it is exposed to blue light. This makes it possible, for the first time, to restrict its action to particular sites – and to inactivate it at will, since the reaction is reversible,” Thorn-Seshold explains. “With this optical switch, we have extended the range of photopharmacology to yet another highly dynamic functional system that is common to all multicellular organisms – the cytoskeleton,” Trauner adds.

Opens external link in new windowFull Press release LMU (English)

Opens external link in new windowVollständige Pressemitteilung LMU (deutsch)

Opens external link in new windowPublication "Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death"