Methylnaltrexone, a peripherally acting opioid receptor antagonist, enhances tumoricidal effects of 5-Fu on human carcinoma cells.
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.


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 muM alone on SW-480 cells (63.5+/-1.1%), on MCF-7 cells (58.3+/-3.1%), or on non-small cell lung cancer cells (81.3+/-1.6%), 5-FU 10 muM plus methylnaltrexone 1.0 muM reduced cancer cell growth in all three cell lines to 50.2+/-2.9% for SW-480 cells (p<0.05), 50.0+/-1.7% for MCF-7 cells (p<0.05) and 68.7+/-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 muM, reduced SW-480 cell growth to 81.9+/-3.7% (p<0.01), MCF-7 cell growth to 85.9+/-2.4% (p<0.01) and lung cancer cell growth to 85.5+/-2.2% (p<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 muM methylnaltrexone for 48 h. However, methylnaltrexone increased the number of cells in the G(1)-phase and decreased the expression of cyclin A.


CONCLUSIONS
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.
Wang
Chong-Zhi
CZ
Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA.
Li
Xiao-Li
XL
Sun
Shi
S
Xie
Jing-Tian
JT
Aung
Han H
HH
Tong
Robin
R
McEntee
Eryn
E
Yuan
Chun-Su
CS
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019925:Cyclin A / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D000644:Quaternary Ammonium Compounds / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D019925:Cyclin A; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009271:Naltrexone; D016650:Fluorescein-5-isothiocyanate; D005472:Fluorouracil