Activation of calcium channels results in a fatal influx of calcium ions into tumor cells.
Calcium ions play a crucial role in cellular functions, yet can become harmful at elevated levels. Researchers have recently developed a compound that targets and destroys tumor cells by regulating the influx of calcium within the cell. This innovative approach utilizes the calcium ions already existing within the tumor tissue, eliminating the need for an external calcium source. The findings of this research were detailed in a paper published in the journal Angewandte Chemie.
Biological cells need calcium ions, among other things, for the proper functioning of the mitochondria, the powerhouses of the cells. However, if there is too much calcium, the mitochondrial processes become unbalanced and the cell suffocates. A research group led by Juyoung Yoon of Ewha Womens University in Seoul, South Korea, together with teams from 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 tumor cell.
Mechanism of the Antitumor Drug
The researchers targeted two channels, the first one in the outer membrane, and the other was 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 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 opens the outer membrane calcium channel, the researchers used the dye indocyanine green. This bioactive agent can be activated by irradiation with near-infrared light, which not only triggers reactions that lead to ROS, but it also heats up the environment. The team explains that the high local temperature activates the other active agent, BNN-6, to release nitric oxide molecules that open the channel in the endoplasmic reticulum.
Following successful trials in tumor cell lines, the team tested an injectable formulation in tumor-implanted mice. To create a biocompatible combined 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 tumor cells and transported into the cell. After injecting the beads into the bloodstream of the mice, the researchers observed 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 that received the preparation.
The authors emphasize that this ion influx approach may also be useful in related biomedical research areas where a similar mechanism could activate ion channels different from calcium in order to find new therapeutic approaches.
Reference: “Photo-Controlled Calcium Overload from Endogenous Sources for Tumor Therapy” by Jing-Jing Hu, Lizhen Yuan, Yunfan Zhang, Jing Kuang, Wen Song, Xiaoding Lou, Fan Xia and Juyoung Yoon, 08 January 2024, Angewandte Chemie International Edition.
The study was funded by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and the National Research Foundation of Korea.