Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil
| Autor: | Stig O. P. Jacobsson, Maria Jonsson, Sofia B. Gustafsson, Theres Lindgren |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
AM251
Antimetabolites Antineoplastic Cancer Research Cannabinoid receptor Cell Survival Adenocarcinoma Pharmacology Biology Toxicology Antioxidants chemistry.chemical_compound Piperidines Cyclic AMP Tumor Cells Cultured medicine Humans Pharmacology (medical) Dronabinol Enzyme Inhibitors Receptors Cannabinoid Cannabinoid Receptor Antagonists Cell Proliferation chemistry.chemical_classification Cannabinoids Drug Synergism Anandamide Endocannabinoid system Oxidative Stress NG-Nitroarginine Methyl Ester Neuroprotective Agents Oncology chemistry Colonic Neoplasms Cancer cell Fatty Acids Unsaturated Pyrazoles Cannabinoid receptor antagonist Drug Therapy Combination Arachidonic acid Fluorouracil Nitric Oxide Synthase Thymidine Polyunsaturated fatty acid medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 63:691-701 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-008-0788-5 |
| Popis: | Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [(3)H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, alpha-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink