Drug, Nembutal can suppress activity in colon cancer cells

Mar 30 2004

A barbiturate once commonly used to treat anxiety may play a role in controlling the spread of colon cancer, say researchers from The University of Texas M. D. Anderson Cancer Center.

Their experimental model of colon cancer — work done in cell cultures and animal studies — demonstrates that the drug, Nembutal, can suppress activity in colon cancer cells the same way it inhibits certain kinds of neurotransmissions in the brain and central nervous system.

The results, presented at the annual meeting of the American Association for Cancer Research, suggest a novel approach to treatment of cancers now known to have neurotransmitter receptors on the outside of their cells. That includes, to date, colon and some ovarian cancers.

“This is the first experimental evidence that Nembutal is a potent inhibitor of colon cancer metastasis,” says the study’s first author, Premal Thaker, M.D., a clinical fellow in the Department of Gynecologic Oncology. “These findings may have therapeutic implications for treatment, but more work needs to be done before we know that.”

Scientists have only recently discovered that the surfaces of colon cancer cells are studded with receptors for gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter.

Nerve cells, or neurons, communicate by releasing neurotransmitters. These chemical messengers flow onto other neurons that act as receivers. The neurotransmitter attaches to a slot on the neuron, or receptor site. Once attached, different neurotransmitters either trigger "go" signals that allow the message to be passed on to other cells or produce "stop" signals that prevent the message from being forwarded. GABA is the most common message-altering neurotransmitter in the brain, inhibiting the transfer of other neurotransmitters as well as other chemical signals, such as hormones.

Nembutal is a member of the barbiturate family of drugs commonly known as “downers” — acting just like inhibitory GABA neurotransmitters, and therefore are useful in controlling such behavioral and physical ailments as sleeplessness, anxiety, tension, high blood pressure and convulsions.

Now, investigators are studying a “secondary type of nerve ending system” that has been found in the colon and in the ovaries. Both presumably use GABA neurotransmitters to regulate use of such chemicals as hormones.

Thaker and a team of researchers from a number of departments at M. D. Anderson tested whether colon and ovarian cancer cells in the laboratory also contain GABA receptors, and what effect use of Nembutal would have on those cells.  

They found that, indeed, the cell lines did contain GABA receptors, and when treated with Nembutal, those cells showed a “four fold” reduction in cyclic AMP, a cellular messenger molecule triggered by hormones or other signaling molecules.

The investigators then tested the drug in mice that had been injected with colon cancer known to express the GABA receptor, and found that four out of 10 mice treated with Nembutal developed primary tumors, compared to eight of 10 mice that did not receive the drug. And the cancer spread to the liver in only 20 percent of Nembutal treated mice, compared to 80 percent of control animals.

Thaker says a lot more work is needed to characterize which “sub-type of GABA receptor may be important for the results seen in our experimental model as a cancer treatment, but these findings may offer us a new future direction.”