title: G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation.
abstract: Opioid effects on tumor growth have been a controversial topic of discussion. In the present study, morphine inhibited tumor cell proliferation at concentrations of >or=10 micro M. This was primarily caused by inhibition of cell cycle progression from G(1) to S phase. At higher concentrations (>or=500 micro M for 24 h), morphine also caused cell death. In nude mice, morphine significantly reduced the growth of MCF-7 and MDA-MB231 tumors but had no effect on HT-29 tumor growth. In these experiments, morphine plasma concentrations were similar to those found in cancer patients receiving chronic morphine treatment for pain relief (0.9-3.4 micro M). In MCF-7 and MDA-MB231 cells, morphine caused a naloxone (Nx)- and pertussis toxin-sensitive, concentration-dependent increase of GTPase activity, indicating that morphine signals could be transduced by opioid receptors via a G protein. However, the antiproliferative effects of morphine were not antagonized by Nx, pertussis toxin, forskolin, and 8-bromo-cAMP, suggesting that the typical opioid receptor-coupled signaling cascade involving the G(i), adenylyl cyclase, and protein kinase A was not involved. Instead, morphine caused an NH(2)-terminal phosphorylation of p53 at Ser(9) and/or Ser(15) and a stabilization of p53 in MCF-7 cells that express wild-type p53. p53 phosphorylation was not antagonized by Nx and resulted in an increase of p53-dependent proteins including p21, Bax, and the death receptor Fas. Blockade of Fas by Fas-fusion protein or inhibition of caspase 8 resulted in a partial inhibition of morphine-induced apoptosis. In addition, Fas ligand only induced apoptosis when administered together with morphine. However, the sensitivity of the tumor cells toward Fas ligand remained low. HT-29 cells, which express dominant negative p53 and show no increase of GTPase activity when treated with morphine, were less sensitive in vitro and were not affected in vivo. Our results suggest that morphine, alone or in combination with Nx, may reduce the growth of certain tumors, apparently in part through activation of p53.
authors.affiliation: Pharmazentrum Frankfurt, Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany. tegeder@em.uni-frankfurt.de
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
authors.forename: Achim
authors.initials: A
authors.lastname: Schmidtko
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D053418:Death Domain Receptor Signaling Adaptor Proteins; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009020:Morphine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000701:Analgesics, Opioid; D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C485896:PIDD1 protein, human; C414729:Pidd1 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D009020:Morphine; D019204:GTP-Binding Proteins