Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal

Abstract

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter, and GABA receptors have been recently detected on epithelial colon cancer cells. Nembutal (pentobarbital) is a barbiturate with GABA-agonistic effects. We demonstrate that GABA receptors are present on colon cancer cell lines (KM12SM, HT29, RKO). Nembutal (0.1-500 ?g/ml) continuous exposure resulted in an IC50 level of 58 ?g/ml for the KM12SM cells and 120 ?g/ml for the HT29 cells. Nembutal reduced cellular cAMP concentration in colon cancer cells and resulted in a dose and time dependent decrease in MMP-2 and MMP-9 levels. In the KM12SM intracecal injected mice, 9 of 10 mice in the metaphane group developed a primary tumor (mean weight =2.16g + 0.76) compared to 7 of 10 mice in the nembutal group (mean weight = .41g + 0.21, p=0.03). In the KM12SM intrasplenic injected mice, the tumor weight in the spleen was 85% smaller in the nembutal group compared to the metaphane group (p=0.008). In the HT29 injected mice, the metaphane group and nembutal group had similar tumor incidence, but combined tumor weight (primary tumor and liver metastases) was significantly higher in the metaphane group (1.61+ 0.45g) versus 0.07+ 0.05g; p=0.008. The incidence of liver metastases in the nembutal group was zero compared to eight out of nine in the metaphane group. To the best of our knowledge, this is the first evidence that nembutal is a potent inhibitor of primary colon cancer and metastasis. These findings may have therapeutic implications for the treatment of colon and other cancers.