NONCONVENTIONAL OPIOID BINDING-SITES MEDIATE GROWTH INHIBITORY EFFECTS OF METHADONE ON HUMAN LUNG-CANCER CELLS

被引:53
作者
MANECKJEE, R [1 ]
MINNA, JD [1 ]
机构
[1] UNIV TEXAS,SW MED CTR,SIMMONS CANC CTR,DALLAS,TX 75235
关键词
D O I
10.1073/pnas.89.4.1169
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 (+/-)-[H-3]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.
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页码:1169 / 1173
页数:5
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