Antiproliferative mechanism of a cannabinoid agonist by cell cycle arrest in human gastric cancer cells

Abstract

For gastric cancers, the antineoplastic activity of cannabinoids has been investigated in only a few reports and knowledge regarding the mechanisms involved is limited. We have reported previously that treatment of gastric cancer cells with a cannabinoid agonist significantly decreased cell proliferation and induced apoptosis. Here, we evaluated the effects of cannabinoids on various cellular mediators involved in cell cycle arrest in gastric cancer cells. AGS and MKN-1 cell lines were used as human gastric cancer cells and WIN 55,212-2 as a cannabinoid agonist. Cell cycles were analyzed by flow cytometry and western blotting. Treatment with WIN 55,212-2 arrested the cell cycle in the G0/G1 phase. WIN 55,212-2 also upregulated phospho-ERK1/2, induced Kip1/p27 and Cip1/WAF1/p21 expression, decreased cyclin D1 and cyclin E expression, decreased Cdk 2, Cdk 4, and Cdk 6 expression levels, and decreased phospho-Rb and E2F-1 expression. ERK inhibitor decreased the proportion of G0/G1 phase which was induced by WIN 55,212-2. Inhibition of pAKT led to cell cycle arrest in gastric cancer cells. Cell cycle arrest preceded apoptotic response. Thus, this cannabinoid agonist can reduce gastric cancer cell proliferation via G1 phase cell cycle arrest, which is mediated via activation of the MAPK pathway and inhibition of pAKT.

Novel anti-cancer role of naphthazarin in human gastric cancer cells

“…DMEM supplemented with 10% heat-inactivated fetal bovine serum (FBS, Hyclone), 5% antibiotic-antimycotic (Gibco, Carlsbad, CA). The cell viability assay was seeded in a 6-well plate (3x10 5 cells), and incubated at 37˚C in a 5% CO 2 The following day the membranes were washed for 10 min, 4 times each, and incubated with the secondary antibody: polyclonal anti-rabbit antibody (1:5000, Invitrogen, Carlsbad, CA) or monoclonal anti-mouse antibody (1:5000, Invitrogen). Antigen-antibody complexes were detected by the enhanced chemiluminescence detection system.…”

“…Gastric cancer is one of the most common malignant tumors and the second cause of cancer-related deaths worldwide (1,2). Chemotherapy for gastric cancer has been well developed, but a globally accepted standard chemotherapy and optical regimens have not yet been determined.…”

Targeting cannabinoid receptors in gastrointestinal cancers for therapeutic uses: current status and future perspectives

“…Interestingly, anandamide has been shown to inhibit the growth of COX-2-expressing colorectal cancer cells by inducing cell death in a cannabinoid receptor-independent mechanism [9]. Finally, it should be highlighted that cannabinoid agonists decrease cell viability and proliferation of human gastric adenocarcinoma cell line [10], including 5-FU resistant cells [11], via G1 phase cell cycle arrest which is mediated by activation of the MAPK pathway and inhibition of pAKT [12].…”

Cannabinoid receptor activation inhibits cell cycle progression by modulating 14-3-3β

“…It is well known that cannabinoids are capable of inducing cell cycle arrest in all phases [39]. In gastric cancer cells, treatment with Win 55,212-2 inhibits cell proliferation by arresting the G 0 /G 1 phase and regulating the expression of various cell cycle-regulating proteins, including p27, p21 cyclin D1 and cyclin E [4,40]. Cell proliferation is inhibited by anandamide application in hepatocellular carcinoma.…”