Synthetic ion transporters have been created before, but this is the first time researchers have demonstrated how an influx of salt into a cell triggers cell death. These synthetic ion transporters could point the way to new anticancer drugs while also benefiting patients with cystic fibrosis.
Study co-author Professor Philip Gale, of the University of Southampton, says, "This work shows how chloride transporters can work with sodium channels in cell membranes to cause an influx of salt into a cell. We found we can trigger cell death with salt."
Cells in the human body work hard to maintain a stable concentration of ions inside their cell membranes. Disruption of this delicate balance can 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 is to trigger this self-destruct sequence by changing the ion balance in cells. Unfortunately, when a cell becomes cancerous, it changes the way it transports ions across its cell membrane in a way that blocks apoptosis.
The University of Texas team, led by Professor Jonathan Sessler at Austin's College of Natural Sciences and co-author of the study, 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 chloride transporter tends to use the sodium channels that naturally occur in the cell's membrane, bringing sodium ions along for the ride.
The University of Southampton team, led by Gale, found that the ion transporters were effective in a model system using artificial lipid membranes.
Professor Injae Shin of Yonsei University 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."
However, the researchers found that their synthetic molecule triggers programmed cell death in both cancerous and healthy cells. To be useful in treating cancer, a version of a chloride transporter will have to be developed that binds only to cancerous cells.
Citation: Sung-Kyun Ko, Sung Kuk Kim, Andrew Share, Vincent M. Lynch, Jinhong Park, Wan Namkung, Wim Van Rossom, Nathalie Busschaert, Philip A. Gale, Jonathan L. Sessler&Injae Shin, "Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells", Nature Chemistry (2014) doi:10.1038/nchem.2021