New drug kills tumor cells by triggering a deadly calcium storm

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Calcium ions are essential for cells, but can be toxic in high concentrations. A team of researchers has now designed and prepared a combination drug that kills tumor cells by modulating the flow of calcium into cells. An external calcium source is not required because calcium ions already present in the tissue are used, according to research published in the journal Angewand Tumor Chem.

Mitochondria, the cell’s powerhouse, require calcium ions, among other things, for the proper functioning of biological cells. However, if there is too much calcium, mitochondrial processes become unbalanced and the cell suffocates. A research team led by Jooyoung Yun of Eva Women’s University in Seoul, South Korea, together with teams in China, has now taken advantage of this process and developed a synergistic antitumor drug that can open calcium channels and thus trigger a deadly calcium storm inside the calcium. Tumor cells.

The researchers observed two channels, the first in the outer membrane and the other a calcium channel in the endoplasmic reticulum, a cell organelle that also stores calcium ions. The channel located in the outer membrane opens when it is exposed to large amounts of reactive oxygen species (ROS), while the channel in the endoplasmic reticulum is activated by nitric oxide molecules.

To generate ROS to open outer membrane calcium channels, the researchers used the dye indocyanine green. This bioactive agent can be activated by irradiation with near-infrared light, which not only triggers reactions leading to ROS, but also heats the environment. The team explains that the high local temperature activates another activating agent, BNN-6, to release nitric oxide molecules that open the channel in the endoplasmic reticulum.

After successful testing in tumor cell lines, the team tested an injectable formulation in tumor-transplanted mice. To create a biocompatible combination drug, the researchers loaded active ingredients into tiny modified porous silica beads that are harmless to the body, but can be recognized by tumor cells and transported into cells. After the beads were injected into the bloodstream of the mice, the researchers found that the drug accumulated in the tumors. Exposure to near-infrared light successfully triggered the process, and the tumor disappeared after a few days in mice receiving the preparation.

The authors emphasize that this ion influx approach could also be useful in related biomedical research where a similar mechanism could activate ion channels other than calcium to search for new therapeutic approaches.

Source:

Journal Reference:

Hu, J.-J., etc. (2024). Photo-regulated calcium overload from endogenous sources for tumor therapy. Angewandte chemi. doi.org/10.1002/anie.202317578.



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