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Cells in the body work hard to maintain a stable concentration of ions inside their cell membranes. Disruption of this delicate balance could trigger cells to go through apoptosis, known as programmed cell death, a mechanism the body uses to rid itself of damaged or dangerous cells.
One way of destroying cancer cells would be to trigger this innate self-destruct sequence by disrupting the ion balance in cells.
An ion is an atom or molecule in which has an unequal number of electrons and protons. This gives the atom a positive or negative electrical charge.
Researchers from The University of Texas at Austin and five other institutions have created a molecule that can cause cancer cells to self-destruct by ferrying sodium and chloride ions into the cancer cells.
These synthetic ion transporters, described this week in the journal Nature Chemistry, confirm a two-decades-old hypothesis that could point the way to new anticancer drugs while also benefiting patients with cystic fibrosis.
Synthetic ion transporters have been created before, but this is the first time researchers have shown them working in a real biological system where transported ions demonstrably cause cells to self-destruct.
Almost two decades ago, a natural substance called prodigiosin was discovered that acted as a natural ion transporter and has an anticancer effect.
Since then, it has been a “chemist’s dream,” said Jonathan Sessler, professor in The University of Texas at Austin's College of Natural Sciences and co-author of the study, to find “synthetic transporters that might be able to do exactly the same job, but better, and also work for treating diseases such as cystic fibrosis where chloride channels don't work.”
Sessler and his collaborators, led by professors Injae Shin of Yonsei University and Philip A. Gale of the University of Southampton and King Abdulaziz University, were able to bring this dream to fruition.
The University of Texas members of the team created a synthetic ion transporter that binds to chloride ions. The molecule works by essentially surrounding the chloride ion in an organic blanket, allowing the ion to dissolve in the cell’s membrane, which is composed largely of lipids, or fats. The researchers found that the transporter tends to use the sodium channels that naturally occur in the cell’s membrane, bringing sodium ions along for the ride.
Gale and his team found that the ion transporters were effective in a model system using artificial lipid membranes.
Shin and his working group were then able to show that these molecules promote cell death in cultured human cancer cells. One of the key findings was that the cancer cell’s ion concentrations changed before apoptosis was triggered, rather than as a side effect of the cell’s death.
“We have thus closed the loop and shown that this mechanism of chloride influx into the cell by a synthetic transporter does indeed trigger apoptosis,” said Sessler. “This is exciting because it points the way towards a new approach to anticancer drug development.”
This research was able to show that the studied sodium and chloride molecules promoted cell death in cultured human cancer cells.