title: Cell death sensitization of leukemia cells by opioid receptor activation.
abstract: Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein-coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies.
authors: Center for Biomedical Research, University of Ulm, Ulm, Germany. claudia.friesen@uni-ulm.de
authors: Claudia
authors: C
authors: Friesen
authors: Mareike
authors: M
authors: Roscher
authors: Inis
authors: I
authors: Hormann
authors: Iduna
authors: I
authors: Fichtner
authors: Andreas
authors: A
authors: Alt
authors: Ralf A
authors: RA
authors: Hilger
authors: Klaus-Michael
authors: KM
authors: Debatin
authors: Erich
authors: E
authors: Miltner
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation; D004317:Doxorubicin / Q000097:blood / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D008297:Male; D008691:Methadone / Q000097:blood / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011957:Receptors, Opioid / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000701:Analgesics, Opioid; D000903:Antibiotics, Antineoplastic; D011957:Receptors, Opioid; D004317:Doxorubicin; D000242:Cyclic AMP; D020169:Caspases; D000262:Adenylyl Cyclases; D008691:Methadone
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