Abstract
Researchers have created a family of light-activated microtubule inhibitors that triggered mitotic arrest and apoptosis. The compounds, which can be switched on and off by different wavelengths of light, killed cultured breast cancer cells and caused microtubules in mouse muscle tissue to break down.
Researchers have developed a new approach that might reduce the side effects of chemotherapy: light-sensitive molecules that they can activate inside tumor cells.
Paclitaxel, vinblastine, and related chemotherapies kill cancer cells by disrupting microtubule activity. However, these compounds also affect healthy cells, and they can trigger side effects such as immune suppression, anemia, and nerve damage. To try to sidestep these problems, a team led by Oliver Thorn-Seshold, PhD, and Dirk Trauner, PhD, of Ludwig Maximilians University in Munich, Germany, designed microtubule-targeting molecules that they can switch on and off by using light (Cell 2015;162:403–11).
The researchers' starting point was combretastatin A-4, a molecule that blocks microtubule polymerization and has been tested in clinical trials against a variety of tumor types. They modified the molecule so that different wavelengths of light flip it from one isomer to the other.
“It's like we have a hinge connecting two parts of the molecule,” says Thorn-Seshold. Blue light pushes the hinge in one direction, activating the drug. Green light pushes the hinge in the opposite direction, switching off the drug. Using this principle, the researchers created a family of inhibitors that they called photostatins.
The scientists added the inhibitors to cultures of breast cancer cells and then either exposed the cells to brief pulses of blue light or kept them in the dark. Photostatins exposed to blue light were 250 times more cytotoxic, triggering mitotic arrest and apoptosis. Flashing the cells with green light immediately after blue-light exposure allowed mitosis to resume.
The researchers also assessed the effects of the inhibitors on microtubules in mouse muscle tissue. After the team soaked the tissue with a photostatin and switched on the blue light, the microtubules collapsed.
Treating tumors that lie in or just beneath the skin is one potential application of the light-activated microtubule inhibitors, but they could target tumors deep within the body, out of reach of light shined on the skin.
Surgically implanted devices could illuminate these tumors, says Thorn-Seshold, and endoscopes and even fiber-optic strands could provide access to localized cancers. The inhibitors are more specific than traditional chemotherapy because they are much more toxic to cells that have been exposed to blue light. Shining green light on healthy cells around a tumor could provide additional protection by switching off inhibitors the cells have absorbed, the researchers suggest. They are beginning tests of photostatins in animals.
When exposed to blue light, photostatins turned on, triggering mitosis and apoptosis (lower right). When exposed to green light, photostatins shut off, allowing mitosis to resume.
When exposed to blue light, photostatins turned on, triggering mitosis and apoptosis (lower right). When exposed to green light, photostatins shut off, allowing mitosis to resume.
“It's exciting, and it's an outstanding first step,” says Erik Dreaden, PhD, of the Massachusetts Institute of Technology in Cambridge. One potential improvement, he says, would be designing molecules that switch on in response to near-infrared light, which penetrates deeper into tissue than does blue light.
“If the wavelengths [for switching on the drugs] could be extended further whilst retaining the control over cytotoxicity, I think this would lead to strong drug candidates for the next generation of light-activated drugs,” adds Nicola Farrer, PhD, of the University of Oxford in the United Kingdom.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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