Photoswitchable Inhibitors of Microtubule Dynamics Optically Control Mitosis and Cell Death

Abstract

Small molecules that interfere with microtubule dynamics, such as Taxol and the Vinca alkaloids, are widely used in cell biology research and as clinical anticancer drugs. However, their activity cannot be restricted to specific target cells, which also causes severe side effects in chemotherapy. Here, we introduce the photostatins, inhibitors that can be switched on and off in vivo by visible light, to optically control microtubule dynamics. Photostatins modulate microtubule dynamics with a subsecond response time and control mitosis in living organisms with single-cell spatial precision. In longer-term applications in cell culture, photostatins are up to 250 times more cytotoxic when switched on with blue light than when kept in the dark. Therefore, photostatins are both valuable tools for cell biology, and are promising as a new class of precision chemotherapeutics whose toxicity may be spatiotemporally constrained using light.

Designing dynamic functional molecular systems

“…Photopharmacology relies on the incorporation of a photoswitch into a drug in order to regulate its activity by irradiation and this relatively new field has been well reviewed elsewhere. Usually, this approach involves small bioactive molecules such as antibiotics 76 and chemotherapy agents, 77 but some examples involve peptides or proteins. Trauner, Isacoff and coworkers developed a photoswitchable linker that could regulate the opening and closing of a Light-gated Ionotropic Glutamate Receptor (LiGluR), a receptor involved in vision.…”

Progress and challenges in electrically pumped GaN-based VCSELs

“…In medical treatment, a technique has recently been developed which uses blue light to activate chemotherapy drugs in specific cells, which could lead to more effective chemotherapy for cancer treatment with limited side effects. 26 To summarize, even though there are no commercial GaN-based VCSELs yet, there are many applications which would benefit from such a light source, and most likely more applications will appear once such light source is available. It is also encouraging to see many companies investing time and effort into this field, and as a result Nichia 27 , Panasonic 28 and Sony 29 now all have demonstrated electrically injected GaN-VCSELs.…”

Optical control over monomeric and multimeric protein hybrids

“…PST-1 is only active in its cis form, hence allowing photo-regulated inhibition of microtubule assembly. Reprinted with permission from ref [78]. Copyright © 2015, Elsevier Inc.…”

“…[77] Replacing the C=C bond in the CA4 structure with N=N bond to mimic azobenzene (Figure 2.5c) results in a photo-active derivative of CA4 called the photostatins (PST). [78] PST switches from its inactive trans to active cis form upon irradiation at λ = 390 -430 nm, which is reversible upon irradiation at λ = 500 -530 nm or by thermal relaxation (in the dark, half-life = 6 min), allowing a fully reversible control over the drug cytotoxicity. The activity of the trans form in the dark is about 250-fold less compared to the cis form upon irradiation with blue light.…”

“…This remarkable difference has been demonstrated to photo-modulate the mictrotubule dynamic assembly in live cells of C. elegans embryo. [78] 2.4 Photo-responsive artificial protein-based systems and…”