diprenorphine and Breast-Neoplasms

In many cancer cell lines, including breast, prostate, lung, brain, head and neck, retina, and the gastrointestinal tract, opioids decrease cell proliferation in a dose-dependent and reversible manner. Opioid and/or other neuropeptide receptors mediate this decrease. We report that only the steroid-hormone-sensitive cell lines MCF7 and T47D respond to opioid growth inhibition in a dose-dependent manner. Therefore, an interaction of the opioid and steroid receptor system might exist, as is the case with insulin. To investigate this interaction, we have assayed two estrogen-inducible proteins (pS2 and the lysosomal enzyme cathepsin D) in MCF7 and T47D cells. When cells were grown in the presence of FBS (in which case a minimal quantity of estrogens and/or opioids is provided by the serum), we observed either no effect of etorphine or ethylketocyclazocine (EKC) or an increase of secretion and/or production of pS2 and cathepsin D. However, when cells were cultured in charcoal-stripped serum and in the absence of phenol red, the effect of the two opioids is different: EKC decreased the production and/or secretion of pS2 and cathepsin D, whereas etorphine increased their synthesis and/or secretion. The differential effect of the two general opioids was attributed to their different receptor selectivity. Furthermore, the variations of the ratio of secreted/produced protein and the use of cycloheximide indicate that opioids selectively modify the regulatory pathway of each protein discretely. In conclusion, through the interaction with opioid and perhaps other membrane-receptor sites, opioid agonists modify in a dose-dependent manner the production and the secretion of two estrogen-regulated proteins. Opioids may therefore disturb hormonal signals mediated by the estrogen receptors. Hence, these chemicals may have potential endocrine disrupting activities.

Topics: Breast Neoplasms; Cathepsin D; Cell Division; Cycloheximide; Cytosol; Diprenorphine; Dose-Response Relationship, Drug; Estradiol; Ethylketocyclazocine; Etorphine; Female; Humans; Inhibitory Concentration 50; Narcotic Antagonists; Narcotics; Neoplasms, Hormone-Dependent; Protein Synthesis Inhibitors; Proteins; Trefoil Factor-1; Tumor Cells, Cultured; Tumor Suppressor Proteins

In the T47D human breast cancer cell line, Taxol was found to compete for ethylketocyclazocine opioid binding (IC50 3.3 pM). In contrast, no interaction of the drug with [3H]diprenorphine binding occurred. Binding was multiphasic, in the absence of colchicine (10[-6] M), but monophasic in its presence, indicating an involvement of the cytoskeleton in this process. Alignment of Taxol binding domains on alpha and beta tubulin with the kappa opioid site revealed homology of these sites with the first extracellular loop of the receptor. These results indicate a possible new action of Taxol, indicating for the first time a membrane action of the agent.

Topics: Amino Acid Sequence; Analgesics, Opioid; Antineoplastic Agents, Phytogenic; Binding Sites; Binding, Competitive; Breast Neoplasms; Diprenorphine; Ethylketocyclazocine; Humans; Molecular Sequence Data; Paclitaxel; Receptors, Opioid; Receptors, Opioid, kappa; Sequence Alignment; Tubulin; Tumor Cells, Cultured

A new casomorphin pentapeptide (alpha S1-casomorphin) has been isolated from the sequence of human alpha S1-casein [alpha S1-casein-(158-162)], with the sequence Tyr-Val-Pro-Phe-Pro. This peptide was found to bind with high affinity to all three subtypes of the kappa-opioid receptor (kappa 1-kappa 2). When amidated at the C-terminus, alpha S1-casomorphin amide binds to the delta- and kappa 3-opioid sites. Both alpha S1-casomorphin and its amide inhibit in a dose-dependent and reversible manner the proliferation of T47D human breast cancer cells. This anti-proliferative activity was greater for alpha S1-casomorphin, which was the most potent opioid in inhibiting T47D cell proliferation. In T47D breast cancer cells, other casomorphins have been found to bind to somatostatin receptors in addition to opioid sites. In contrast, alpha S1-casomorphin and its amide do not interact with somatostatin receptors in our system.

Topics: Amino Acid Sequence; Binding, Competitive; Breast Neoplasms; Caseins; Cell Division; Cell Line; Diprenorphine; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Ethylketocyclazocine; Female; Humans; Kinetics; Peptide Fragments; Receptors, Opioid, kappa