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Cell death sensitization of leukemia cells by opioid receptor activation

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Item Type:Article
Title:Cell death sensitization of leukemia cells by opioid receptor activation
Creators Name:Friesen, C. and Roscher, M. and Hormann, I. and Fichtner, I. and Alt, A. and Hilger, R.A. and Debatin, K.M. and Miltner, E.
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.
Keywords:Opioids, Methadone, Doxorubicin, cAMP, Apoptosis, Acute Lymphoblastic Leukemia, Animals, Mice
Source:Oncotarget
ISSN:1949-2553
Publisher:Impact Journals (U.S.A.)
Volume:4
Number:5
Page Range:677-690
Date:16 April 2013
Official Publication:http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=952&path[]=1292
PubMed:View item in PubMed

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