jzl-184 and Colorectal-Neoplasms

The endocannabinoid system has previously been shown to play a role in the permeability and inflammatory response of the human gut. The goal of our study was to determine the effects of endogenous anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) on the permeability and inflammatory response of intestinal epithelium under normal, inflammatory, and hypoxic conditions. Human intestinal mucosa was modeled using Caco-2 cells. Human tissue was collected from planned colorectal resections. Accumulation of AEA and 2-AG was achieved by inhibiting their metabolizing enzymes URB597 (a fatty acid amide hydrolase inhibitor) and JZL184 (a monoacylglycerol lipase inhibitor). Inflammation and ischemia were simulated with TNF-α and IFN-γ and oxygen deprivation. Permeability changes were measured by transepithelial electrical resistance. The role of the CB

Topics: Amidohydrolases; Arachidonic Acids; Benzamides; Benzodioxoles; Caco-2 Cells; Carbamates; Colorectal Neoplasms; Cytokines; Electric Impedance; Endocannabinoids; Gene Expression Regulation; Glycerides; Humans; Inflammation; Intestinal Mucosa; Intestines; Monoacylglycerol Lipases; Oxygen Consumption; Permeability; Piperidines; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Tissue Culture Techniques

Monoacylglycerol lipase (MAGL) is involved in the degradation of triacylglycerol. Previous studies have demonstrated that MAGL regulates tumor growth and metastasis via fatty acid networks, and is associated with colorectal cancer. JZL184 is a MAGL inhibitor, which in the present study was administered to colorectal cancer cell lines, resulting in decreased tumor proliferation, increased apoptosis and increased tumor cell sensitivity to 5-fluorouracil. B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax) are key proteins in apoptosis. The expression levels of Bcl‑2/Bax were determined in colorectal cancer cell lines following JZL184 administration, and it was observed that the mRNA and protein expression levels of Bcl‑2 were decreased, whereas the expression levels of Bax were increased. These results indicated that JZL184 may induce tumor cell apoptosis by regulating the expression of Bcl‑2 and Bax. Epithelial-mesenchymal transition (EMT) is closely associated with metastasis. Administration of JZL184 in various malignant colorectal cancer cell lines suppressed migration and altered the expression of EMT markers; E‑cadherin was increased, whereas the expression levels of vimentin and zinc finger protein SNAI1 were decreased. These results suggested that JZL184 was able to regulate the EMT process, in order to control the migration of colorectal cancer cells, particularly in tumors with a stronger metastatic capability. Therefore, in colorectal cancer, MAGL may be considered a potential therapeutic target and JZL184 may be a possible therapeutic agent.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Benzodioxoles; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Monoacylglycerol Lipases; Piperidines; Proto-Oncogene Proteins c-bcl-2