TY - JOUR
T1 - Nonconventional opioid binding sites mediate growth inhibitory effects of methadone on human lung cancer cells
AU - Maneckjee, Rhoda
AU - Minna, John D.
PY - 1992/2/15
Y1 - 1992/2/15
N2 - 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 κ, phencyclidine, σ, but not μ, and δ 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.
AB - 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 κ, phencyclidine, σ, but not μ, and δ 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.
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U2 - 10.1073/pnas.89.4.1169
DO - 10.1073/pnas.89.4.1169
M3 - Article
C2 - 1311082
AN - SCOPUS:0026547233
SN - 0027-8424
VL - 89
SP - 1169
EP - 1173
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
ER -