Lay Summary by Grant Simpson
The biggest restriction on cancer chemotherapy is the off-target damage it causes to healthy cells, which often results in dreadful and therapeutically-limiting side effects. Chemists from the Ludwig-Maximilians-Universität München (LMU) in Germany have now developed a new principle for cytotoxic (cell-killing) chemotherapeutic compounds, using a built-in molecular switch that can be reversibly activated and deactivated, using pulses of blue- and green-colored light, to precisely target cancer cells with even single-cell fidelity. By rapidly activating the cytotoxic properties using blue light only inside solid tumors, and deactivating the compound elsewhere, these compounds would avoid collateral damage to surrounding healthy cells: making them promising candidates for a new era of light-targeted chemotherapeutics.
To achieve this, they took the known cytotoxic drug Combretastatin A-4 (CA4) and installed a molecular switch which, when exposed to light, dramatically changes the geometry of the compound to either an active or inactive configuration. The molecular structure of CA4 can be thought of like a butterfly, each “wing” being a benzene ring with small methoxy groups attached. The “wings” of the toxic CA4 are rigidly held in place by a carbon-carbon double bond with the tips pointing in the same direction, i.e. the cis confirmation. The new “photostatin” compounds from Munich contain an azo bond (nitrogen-nitrogen double bond), which bridges the two “wings” and functions as the light-controlled molecular switch. The photostatins are naturally in a relaxed and biologically inactive trans conformation (with the tips of the “wings” pointing in opposite directions), but when pulsed with blue light the azo bond instantaneously converts to the toxic cis conformation. The photostatins spontaneously relax to the trans confirmation when left in the dark, but can be induced to relax with green light illumination as well. Much like how the shape of a key is critical to opening a lock, when the photostatins are in the cis confirmation, they possess the same shape and therefore similar cytotoxicity as CA4, but when in the trans confirmation the compounds do not harm cells.
Like the CA4 compound they paralleled, they robustly demonstrate their photostatins work to kill the cell through disrupting the formation of intracellular microtubules, a vital component of cell structure and cell growth/division. They show in a variety of cancer cell lines and tissues treated with photostatin, that microtubules stop growing in less than a second when pulsed with blue light, and restart growing when pulsed with green light (video at cell.com). Compared to CA4, the blue-illuminated photostatins need higher concentrations to disrupt microtubules and cause cell death, but — the crucial distinction — when cells treated with photostatins are kept in the dark or illuminated with green light, the cells remain perfectly healthy.
They envision that the spontaneous cis (active) to trans (inactive) conversion of the photostatins should act as a safety mechanism by reducing the effects on healthy cells to accidentally-activated photostatin. They also suggest it may be possible to use dual light illumination to form a photo-active zone of toxicity targeted at a solid tumor (with blue light illumination), and a surrounding “protective belt zone” of photo-deactivation (with green light illumination) that would deactivate any photostatins that might leak out from the tumor into the body. With the ultimate goal of side-effect-free curative chemotherapy in sight, these new compounds provide a promising new way to precisely target cancer areas, meaning less unpleasant chemotherapeutic side effects and more people making a full recovery from cancer.
For further information
Read the Cell original research article which this summary is based on Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death (July 2015).
Visit the profile of the research ambassador, Grant Simpson, who wrote this summary.
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