A scientific team from the Institute of Advanced Chemistry of Catalonia (IQAC), part of the Spanish National Research Council (CSIC), in collaboration with the Vall d’Hebron Research Institute (VHIR), has developed a new experimental strategy based on the use of light to activate a chloroquine derivative. This approach succeeds in eliminating tumor cells, including the most resistant ones, known as cancer stem cells, in breast cancer models. The results have been published in the journal ACS Chemical Biology.

“These stem cells, also called cancer stem cells, constitute a particularly problematic subpopulation because they are able to survive conventional treatments and promote tumor relapse. The aim of the study was precisely to find a way to eliminate them selectively,” explains Laia Josa Culleré, author and researcher at IQAC-CSIC.

To achieve this, the team used a photopharmacology approach, a discipline that allows drugs to be activated by light at the desired place and time. In this study, the researchers chemically modified a known compound, chloroquine, a drug used to treat malaria and autoimmune diseases, so that it remains inactive until activated through illumination.

“We design molecules that have no effect in the absence of light, but which, after being stimulated by light, release the active drug and exert their action on tumor cells,” says Sofía Alonso-Manresa, researcher at IQAC-CSIC.

The in vitro experiments carried out in colorectal cancer and head and neck cancer cellular models demonstrated that, after illumination lasting only a few seconds, the activated molecule prevents the formation of three-dimensional structures known as tumor spheres, which represent a model enriched in cancer stem cells.

In the absence of light, these structures form normally. In addition, the study shows that the mechanism of action is related to the inhibition of autophagy, a key cellular process for the survival of these resistant cells.

Validation in an animal model

As proof of concept, the team carried out validation assays in a murine breast cancer model at the U20 unit of Nanbiosis/FVPR*. In these experiments, the molecule was administered directly into the tumor and activated through external illumination.

The results confirmed that activation of the compound occurs when light is applied inside the tumor, but not in darkness, reinforcing the potential of this strategy to act locally and reduce side effects in healthy tissues.

“Cancer stem cells represent one of the main challenges in oncology because they are capable of resisting conventional treatments and promoting tumor recurrence. This work demonstrates that photopharmacology can become a highly promising tool for specifically targeting this cell population in a localized and controlled manner,” highlights Matilde Lleonart, head of the Head and Neck Cancer: Biomedical Research in Cancer Stem Cells group at VHIR.

Toward more precise therapies

Although the work is still at an early stage, the results open the door to the development of new, more selective cancer therapies. The Josa-Culleré team is currently working on optimizing the molecules so that they can be activated with more penetrating wavelengths, such as green or red light, which would facilitate their application in larger and deeper tumors.

“This approach makes it possible to precisely control when and where the drug acts, which could represent a significant advantage over conventional treatments,” notes Amadeu Llebaria, head of the Chemical Medicine and Synthesis group at IQAC-CSIC, where the research was developed.

The research has been funded by national and European projects aimed at developing new therapeutic strategies against cancer.

*Institutional statement on research animals