Laia Josa Culleré, at the Institute of Advanced Chemistry of Catalonia. (Photo: Alejandro Rodriguez)
One limitation of cancer drugs is that they often fail to fully differentiate between cancer cells and healthy cells. This lack of selectivity of current chemotherapy limits its therapeutic window, which decreases the effectiveness of the treatment and causes unwanted side effects.
Photosensitive drugs, whose activity can be precisely controlled by external light and in a reversible manner, can solve this problem, since they provide great control of the site of action and for a desired time, thus reducing side effects and increasing their efficacy. However, today this type of drug is basically in the experimental phase.
Laia Josa Culleré and Amadeu Llebaria, from the Institute for Advanced Chemistry of Catalonia (IQAC), an institution attached to the Higher Council for Scientific Research (CSIC) in Spain, have investigated a series of photosensitive drugs that can be reversibly activated by external light , thus achieving a much more localized and controlled effect. This research suggests that photopharmacology (drugs controlled by light) is capable of opening a new path towards highly specific therapies that could open new avenues for the treatment of diseases such as cancer.
The new study focused on a common target in oncology, histone deacetylase (HDAC) enzymes. When these enzymes are misregulated, they prevent the expression of certain genes, such as tumor suppressors, and therefore in these circumstances, cells are more likely to become cancer cells. For this reason, multiple drugs are being developed aimed at inhibiting poorly regulated HDACs in order to slow the progression of this disease. Currently, there are conventional drugs that act on these enzymes, but they have low selectivity and toxic effects. For this reason, this research focused on designing molecules based on these conventional drugs, but that could be reversibly regulated by light, allowing their activity to be controlled by changes in lighting conditions.
The first results showed that when these molecules were activated by light they inhibited HDACs as opposed to when they were inactive in the dark. The limitation of these first molecules is that to activate they needed ultraviolet light, which can be harmful to cells and has low penetration into biological tissues. Therefore, the molecules were optimized to activate in green light (visible light), also obtaining better results under illumination than in the dark.
Finally, the activity of these molecules was verified in four cancer cell lines: cervix, breast, leukemia and colon. The results showed increased cancer cell death after illumination with green light, but had no effect when kept in the dark. “One of the strengths of the study is that these molecules have been able to activate with visible light (green), while almost all the molecules that are described against cancer are activated with ultraviolet light, which is less effective, and limits the approach to tests in vivo and in patients”, explains Amadeu Llebaria, head of the IQAC Medicinal Chemistry and Synthesis group.
As a result of the study, the researchers have developed a small library of photosensitive drugs that allow cell viability to be controlled only by illuminating them with visible light, which is more permeable and less damaging to cells. It is believed that these results will pave the way for, in the future perhaps closer than we think, to make possible a pharmacological revolution in which light-activatable drugs occupy a prominent position within the drug arsenal of humanity,
The study is titled “Visible-Light-Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy”. And it has been published in the Journal of Medicinal Chemistry. (Source: Ana Sotres / IQAC / CSIC)
Source: NCYT® | (Noticiasdelaciencia.com / Amazings.com)
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