Experimental Drug Kills Cancer Cells by Interfering with Their Ion Transport Mechanism

An experimental anticancer drug induces cells to enter a molecular pathway leading to apoptosis by skewing their ion transport systems to greatly favor the influx of chloride anions.

To promote development of low molecular weight ion transporter drugs, investigators at The University of Texas, Austin (USA) sought to show that there was a direct correlation between a change in cellular chloride anion concentration and cytotoxicity for synthetic ion carriers.

To accomplish this goal, the investigators and their colleagues from five other research institutes created two synthetic ion transporters—pyridine diamide-strapped calix[4]pyrroles—that bind to chloride ions.

Results published in the August 11, 2014, online edition of the journal Nature Chemistry revealed that these compounds induced coupled chloride anion and sodium cation transport in both liposomal models and cells, and promoted cell death by increasing intracellular chloride and sodium ion concentrations. Removing either ion from the extracellular media or blocking natural sodium channels prevented this effect.

“We have demonstrated that this mechanism is viable, that this idea that has been around for over two decades is scientifically valid, and that is exciting,” said contributing author Dr. Jonathan L. Sessler, professor of chemistry at the University of Texas, Austin. “We were able to show sodium is really going in, chloride is really going in. There is now, I think, very little ambiguity as to the validity of this two-decades-old hypothesis. We have shown that this mechanism of chloride influx into the cell by a synthetic transporter does indeed trigger apoptosis. This is exciting because it points the way towards a new approach to anticancer drug development.”

The synthetic molecules described in the current study induce programmed cell death in both cancerous and healthy cells. To be of any value in treating cancer, a version of a chloride anion transporter will have to be developed that acts only on cancer cells.

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