Methadone, Commonly Used as Maintenance Medication for Outpatient Treatment of Opioid Dependence, Kills Leukemia Cells and Overcomes Chemoresistance

Abstract

The therapeutic opioid drug methadone (D,L-methadone hydrochloride) is the most commonly used maintenance medication for outpatient treatment of opioid dependence. In our study, we found that methadone is also a potent inducer of cell death in leukemia cells and we clarified the unknown mechanism of methadone-induced cell killing in leukemia cells. Methadone inhibited proliferation in leukemia cells and induced cell death through apoptosis induction and activated apoptosis pathways through the activation of caspase-9 and caspase-3, down-regulation of Bcl-x L and X chromosome-linked inhibitor of apoptosis, and cleavage of poly(ADP-ribose) polymerase. In addition, methadone induced cell death not only in anticancer drug-sensitive and apoptosis-sensitive leukemia cells but also in doxorubicinresistant, multidrug-resistant, and apoptosis-resistant leukemia cells, which anticancer drugs commonly used in conventional therapies of leukemias failed to kill. Depending on caspase activation, methadone overcomes doxorubicin resistance, multidrug resistance, and apoptosis resistance in leukemia cells through activation of mitochondria. In contrast to leukemia cells, nonleukemic peripheral blood lymphocytes survived after methadone treatment. These findings show that methadone kills leukemia cells and breaks chemoresistance and apoptosis resistance. Our results suggest that methadone is a promising therapeutic approach not only for patients with opioid dependence but also for patients with leukemias and provide the foundation for new strategies using methadone as an additional anticancer drug in leukemia therapy, especially when conventional therapies are less effective. [Cancer Res 2008;68(15):6059-64]

Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

“…We recently published that the µ-opioid receptor agonist D,L-methadone breaks chemo- and radioresistance in leukemia cells expressing opioid receptors and sensitizes leukemia cells for doxorubicin treatment 12 , 13 . Doxorubicin is an effective substance in treatment of malignant gliomas in in vitro studies and animal models 22 .…”

“…D,L-methadone is an µ-opioid receptor agonist inducing apoptosis in leukemia cells in vitro and in vivo 12 - 14 . In addition, D,L-methadone sensitizes leukemia cells for doxorubicin treatment via downregulation of cAMP triggered by opioid receptor activation 13 .…”

Challenging Small Human Hepatocytes with Opiates: Further Characterization of a Novel Prototype Bioartificial Liver

“…Further, positive immunomodulating effects in cancer patients undergoing methadone treatment were reported recently. 24 To prevent serious withdrawal symptoms, these substances must not be abruptly discontinued. As a consequence, it is essential to know the extent to which the present BAL device using SH is able to metabolize morphine and methadone to bridge such patients to liver transplantation.…”

Safety and Tolerance of D,L-Methadone in Combination with Chemotherapy in Patients with Glioma

“…Opioids are substances that act on opioid receptors. Opioid receptor activation initiates a cascade of events resulting in a diversity of biological effects such as analgesia and sedation but also has effects on cell survival and proliferation (4)(5)(6)(7). Opioid receptor stimulation can activate inhibitory G i -proteins, which in turn block adenylyl cyclase activity, reducing cyclic adenosine monophosphate (cAMP) ( Figure 1) (8).…”

“…This effect is most pronounced with D,Lmethadone since D-methadone stabilizes the opioid receptors and thus facilitates more binding of L-methadone. D,LMethadone also down-regulates expression of anti-apoptotic molecules such as B-cell lymphoma-extra large (BCL-xL) or X-linked inhibitor of apoptosis protein (XIAP) (2,3,7). The effect of D,L-methadone is also dependent on the opioid receptor density on the tumor cell surface and the agent's dosage (2,3).…”