Nonconventional opioid binding sites mediate growth inhibitory effects of methadone on human lung cancer cells.
Methadone was found to significantly inhibit the in vitro and in vivo growth of human lung cancer cells. The in vitro growth inhibition (occurring at 1-100 nM methadone) was associated with changes in cell morphology and viability detectable within 1 hr and was irreversible after a 24-hr exposure to the drug. These effects of methadone could be reversed in the first 6 hr by naltrexone, actinomycin D, and cycloheximide, suggesting involvement of opioid-like receptors and the requirement for de novo mRNA and protein synthesis. The inhibitory effects of methadone on the growth of lung cancer cells also could be achieved by the less addictive (+) isomer of methadone. Characterization of the methadone binding to lung cancer cell membranes revealed high-affinity (nM), saturable binding sites for (+/-)-[3H]methadone, which cross-reacted with ligands for kappa, phencyclidine, sigma, but not mu, and delta opioid receptors, and the binding characteristics appeared to be different from methadone sites present in rat brain. Methadone decreases cAMP levels in lung cancer cells, but the receptors are not coupled to a pertussis toxin-sensitive guanine nucleotide-binding regulatory protein. We conclude that the lung cancer growth inhibitory effects of methadone are significant, occur at low concentrations, and are mediated by a nonconventional type of opioid binding site distinct from methadone receptors found in the brain.
Maneckjee
R
R
National Cancer Institute-Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20889.
Minna
J D
JD
D001665:Binding Sites; D002118:Calcium / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008691:Methadone / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D037342:Pertussis Toxin; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism / Q000502:physiology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D006131:Growth Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D010566:Virulence Factors, Bordetella; D003609:Dactinomycin; D009271:Naltrexone; D009538:Nicotine; D009020:Morphine; D003513:Cycloheximide; D000242:Cyclic AMP; D037342:Pertussis Toxin; D002118:Calcium; D008691:Methadone