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

Premal H. Thaker, Kenji Yokoi, Nicholas B. Jennings, Yang Li, Robert B Rebhun, Dennis L. Rousseau, Dominic Fan, Anil K. Sood

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 (KM1 2SM, HT29, RKO). Nembutal (0.1-500 μg/ml) continuous exposure resulted in an IC50 level of 58 μg/ml for the KM12SM cells and 120 μg/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 = 0.41g ± 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 ± 0.45 g) versus 0.07 ± 0.05 g; 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.

Original languageEnglish (US)
Pages (from-to)753-758
Number of pages6
JournalCancer Biology and Therapy
Volume4
Issue number7
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

GABA Agonists
GABA Receptors
Pentobarbital
Colonic Neoplasms
Neoplasm Metastasis
Tumor Burden
Matrix Metalloproteinases
gamma-Aminobutyric Acid
HT29 Cells
Liver
Incidence
Inhibitory Concentration 50
Neurotransmitter Agents
Neoplasms
Spleen
Weights and Measures
Cell Line

Keywords

  • Colon carcinoma
  • GABA agonist
  • Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Thaker, P. H., Yokoi, K., Jennings, N. B., Li, Y., Rebhun, R. B., Rousseau, D. L., ... Sood, A. K. (2005). Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal. Cancer Biology and Therapy, 4(7), 753-758.

Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal. / Thaker, Premal H.; Yokoi, Kenji; Jennings, Nicholas B.; Li, Yang; Rebhun, Robert B; Rousseau, Dennis L.; Fan, Dominic; Sood, Anil K.

In: Cancer Biology and Therapy, Vol. 4, No. 7, 07.2005, p. 753-758.

Research output: Contribution to journalArticle

Thaker, PH, Yokoi, K, Jennings, NB, Li, Y, Rebhun, RB, Rousseau, DL, Fan, D & Sood, AK 2005, 'Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal', Cancer Biology and Therapy, vol. 4, no. 7, pp. 753-758.
Thaker PH, Yokoi K, Jennings NB, Li Y, Rebhun RB, Rousseau DL et al. Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal. Cancer Biology and Therapy. 2005 Jul;4(7):753-758.
Thaker, Premal H. ; Yokoi, Kenji ; Jennings, Nicholas B. ; Li, Yang ; Rebhun, Robert B ; Rousseau, Dennis L. ; Fan, Dominic ; Sood, Anil K. / Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal. In: Cancer Biology and Therapy. 2005 ; Vol. 4, No. 7. pp. 753-758.
@article{8478ab4a731f432ba37e369289982050,
title = "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 (KM1 2SM, HT29, RKO). Nembutal (0.1-500 μg/ml) continuous exposure resulted in an IC50 level of 58 μg/ml for the KM12SM cells and 120 μg/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 = 0.41g ± 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 ± 0.45 g) versus 0.07 ± 0.05 g; 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.",
keywords = "Colon carcinoma, GABA agonist, Metastasis",
author = "Thaker, {Premal H.} and Kenji Yokoi and Jennings, {Nicholas B.} and Yang Li and Rebhun, {Robert B} and Rousseau, {Dennis L.} and Dominic Fan and Sood, {Anil K.}",
year = "2005",
month = "7",
language = "English (US)",
volume = "4",
pages = "753--758",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Landes Bioscience",
number = "7",

}

TY - JOUR

T1 - Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal

AU - Thaker, Premal H.

AU - Yokoi, Kenji

AU - Jennings, Nicholas B.

AU - Li, Yang

AU - Rebhun, Robert B

AU - Rousseau, Dennis L.

AU - Fan, Dominic

AU - Sood, Anil K.

PY - 2005/7

Y1 - 2005/7

N2 - 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 (KM1 2SM, HT29, RKO). Nembutal (0.1-500 μg/ml) continuous exposure resulted in an IC50 level of 58 μg/ml for the KM12SM cells and 120 μg/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 = 0.41g ± 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 ± 0.45 g) versus 0.07 ± 0.05 g; 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.

AB - 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 (KM1 2SM, HT29, RKO). Nembutal (0.1-500 μg/ml) continuous exposure resulted in an IC50 level of 58 μg/ml for the KM12SM cells and 120 μg/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 = 0.41g ± 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 ± 0.45 g) versus 0.07 ± 0.05 g; 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.

KW - Colon carcinoma

KW - GABA agonist

KW - Metastasis

UR - http://www.scopus.com/inward/record.url?scp=25144521768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=25144521768&partnerID=8YFLogxK

M3 - Article

C2 - 15970706

AN - SCOPUS:25144521768

VL - 4

SP - 753

EP - 758

JO - Cancer Biology and Therapy

JF - Cancer Biology and Therapy

SN - 1538-4047

IS - 7

ER -