@article {WANG2927, author = {CHONG-ZHI WANG and XIAO-LI LI and SHI SUN and JING-TIAN XIE and HAN H. AUNG and ROBIN TONG and ERYN MCENTEE and CHUN-SU YUAN}, title = {Methylnaltrexone, a Peripherally Acting Opioid Receptor Antagonist, Enhances Tumoricidal Effects of 5-FU on Human Carcinoma Cells}, volume = {29}, number = {8}, pages = {2927--2932}, year = {2009}, publisher = {International Institute of Anticancer Research}, abstract = {Background: Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities of chemotherapeutic agents, however, have not been evaluated. In this study, the effect of methylnaltrexone on the action of 5-fluorouracil (5-FU) was tested in three human cancer cell lines. Materials and Methods: Treatment was for 72 h and the effects on cell proliferation were measured in human SW-480 colorectal cancer cells, MCF-7 breast cancer cells and non-small cell lung cancer cells in vitro. The apoptotic effect was analyzed by using flow cytometry. The cell cycle and expression of cyclin A were assayed after staining with propidium iodide and cyclin A-fluorescein isothiocyanate. Results: 5-FU decreased the cancer cell growth significantly in all three cancer cell lines in a concentration-dependent manner and methylnaltrexone enhanced the actions of 5-FU. Compared to 5-FU 10 μM alone on SW-480 cells (63.5{\textpm}1.1\%), on MCF-7 cells (58.3{\textpm}3.1\%), or on non-small cell lung cancer cells (81.3{\textpm}1.6\%), 5-FU 10 μM plus methylnaltrexone 1.0 μM reduced cancer cell growth in all three cell lines to 50.2{\textpm}2.9\% for SW-480 cells (p\<0.05), 50.0{\textpm}1.7\% for MCF-7 cells (p\<0.05) and 68.7{\textpm}2.2\% for lung cancer cells (p\<0.01). Methylnaltrexone alone also showed anti-proliferative activity in the three cell lines. Methylnaltrexone at 1.0 μM, reduced SW-480 cell growth to 81.9{\textpm}3.7\% (p\<0.01), MCF-7 cell growth to 85.9{\textpm}2.4\% (p\<0.01) and lung cancer cell growth to 85.5{\textpm}2.2\% (p\<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 μM methylnaltrexone for 48 h. However, methylnaltrexone increased the number of cells in the G1-phase and decreased the expression of cyclin A. Conclusion: At its therapeutic concentrations for opioid-induced constipation, methylnaltrexone does not attenuate and in fact may enhance the tumoricidal activity of 5-FU. Enhanced 5-FU activity may be attributed to the distinct pathways of 5-FU and methylnaltrexone, an effect that could give methylnaltrexone a complementary role in the treatment of cancer with chemotherapeutic agents.}, issn = {0250-7005}, URL = {https://ar.iiarjournals.org/content/29/8/2927}, eprint = {https://ar.iiarjournals.org/content/29/8/2927.full.pdf}, journal = {Anticancer Research} }