Calcium ions are essential for cells, but can be toxic at higher concentrations. A team of researchers has now designed and manufactured a combination drug that kills cancer cells by regulating the influx of calcium into the cell. An external source of calcium is not necessary because only the calcium ions already present in the tumor tissue are used, according to the study published in the journal Angewandte Chemie.
Biological cells need calcium ions, among other things, for the proper functioning of the mitochondria, the energy production centers of the cells. However, if there is too much calcium, mitochondrial processes become unbalanced and the cell suffocates. A research team led by Juyoung Yoon of Ewha Womens University in Seoul, South Korea, along with teams from China, has now exploited this process and developed a synergistic anticancer drug that can open calcium channels and thus cause a lethal calcium storm inside the cancer cell.
The researchers targeted two channels, the first in the outer membrane and the other a calcium channel in the endoplasmic reticulum, a cellular organelle that also stores calcium ions. The channel located in the outer membrane opens when exposed to a large amount of reactive oxygen species (ROS), while the channel in the endoplasmic reticulum is activated by nitric oxide molecules.
To generate the ROS that open the outer membrane calcium channel, the researchers used the green dye indocyanine. 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 the other active factor, BNN-6, to release nitric oxide molecules that open the channel in the endoplasmic reticulum.
After successful trials in tumor cell lines, the team tested an injectable formulation in mice implanted with a tumor. To create a biocompatible combination drug, the researchers loaded the active ingredients into tiny modified porous silica beads that are not harmful to the body, but can be recognized by cancer cells and transported into the cell. After injecting the pellets into the mice’s bloodstream, the researchers noticed that the drug accumulated in the tumor. Exposure to near-infrared light successfully triggered the mechanism of action, and the tumor disappeared after a few days in mice receiving the formulation.
The authors emphasize that this ion influx approach may also be useful in related areas of biomedical research where a similar mechanism could activate ion channels other than calcium in order to find new therapeutic approaches.