Friesen Claudia, Roscher Mareike, Hormann Inis, Fichtner Iduna, Alt Andreas, Hilger Ralf A, Debatin Klaus-Michael, Miltner Erich
Center for Biomedical Research, University of Ulm, Ulm, Germany.
Oncotarget. 2013 May;4(5):677-90. doi: 10.18632/oncotarget.952.
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.
环磷酸腺苷（cAMP）调节多种细胞过程并调节细胞死亡诱导。在刺激抑制或激活腺苷酸环化酶的特定G蛋白偶联受体后，cAMP水平会发生改变。阿片受体刺激可激活抑制性Gi蛋白，进而阻断腺苷酸环化酶活性，降低cAMP水平。诸如消旋美沙酮之类的阿片类药物可诱导白血病细胞死亡。然而，阿片类药物如何在白血病细胞中触发凋亡并激活半胱天冬酶的机制尚不清楚。在本研究中，我们证明使用阿片类药物消旋美沙酮激活阿片受体所诱导的cAMP下调可杀死白血病细胞并使其对多柔比星治疗敏感。通过阻断阿片受体信号增强cAMP水平可强烈降低消旋美沙酮诱导的凋亡、半胱天冬酶激活及对多柔比星的敏感性。使用阿片类药物消旋美沙酮激活阿片受体诱导白血病细胞死亡取决于细胞表面阿片受体表达的临界水平。多柔比星可增加白血病细胞中阿片受体的表达。此外，阿片类药物消旋美沙酮可增加白血病细胞对多柔比星的摄取并减少其流出，这表明阿片类药物消旋美沙酮以及多柔比星可相互增加其细胞毒性潜力。此外，我们发现单独使用消旋美沙酮或与多柔比星联合使用激活阿片受体在体内可显著抑制肿瘤生长。这些结果表明，通过触发cAMP下调激活阿片受体可诱导凋亡、激活半胱天冬酶并使白血病细胞对多柔比星治疗敏感。因此，激活阿片受体似乎是改善抗癌治疗的一种有前景的策略。
