title: Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma.
abstract: Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas' resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells.
authors.affiliation: Center for Biomedical Research; University of Ulm; Ulm, Germany; Institute of Legal Medicine; University of Ulm; Ulm, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Friesen
authors.affiliation: Center for Biomedical Research; University of Ulm; Ulm, Germany; Institute of Legal Medicine; University of Ulm; Ulm, Germany.
authors.forename: Inis
authors.initials: I
authors.lastname: Hormann
authors.affiliation: Center for Biomedical Research; University of Ulm; Ulm, Germany; Institute of Legal Medicine; University of Ulm; Ulm, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Roscher
authors.affiliation: Max Delbrueck Center for Molecular Medicine; Berlin, Germany.
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.affiliation: Institute of Legal Medicine; University of Ulm; Ulm, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Alt
authors.affiliation: Department of Internal Medicine; University of Essen; West German Cancer Center; Essen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hilger
authors.affiliation: University Children's Hospital; University of Ulm; Ulm, Germany.
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.affiliation: Center for Biomedical Research; University of Ulm; Ulm, Germany; Institute of Legal Medicine; University of Ulm; Ulm, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Miltner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008691:Methadone / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017450:Receptors, Opioid, mu; D004317:Doxorubicin; D000242:Cyclic AMP; D008691:Methadone
keywords: D,L-methadone; apoptosis; cAMP; chemoresistance; chemotherapy; glioblastoma; glioblastoma stem cells; opioid receptor