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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in children but affects adolescents as well [1]
To analyze if cell death induction using D,L-methadone depends on the levels of opioid receptor expression, we treated the xenograftderived ALL cells with different concentrations of D,Lmethadone (Figure 1B)
ALL is a malignant disorder originating from single B- or T-lymphocyte progenitors [1]
Summary
Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in children but affects adolescents as well [1]. Patients suffering from relapse have a poor outcome [4] which is mainly determined by the response to chemotherapy, involving a number of deregulated pathways like differentiation, survival and apoptosis [3, 5,6,7]. The main goal in chemotherapies is the concerted destruction of cells via apoptosis [8, 9]. Apoptosis can be mediated via the external death receptor/ligand pathway or the intrinsic pathway involving caspases [8,9,10]. Proapoptotic proteins like Bax and anti-apoptotic proteins www.impactjournals.com/oncotarget
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