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The search continues for improved therapy for acute lymphoblastic leukemia ( a LL), the most common malignancy in children. Recently,  d , l -methadone was put forth as sensitizer for  a LL chemotherapy. However, the specific target of  d , l -methadone in leukemic cells and the mechanism by which it induces leukemic cell apoptosis remain to be defined. Here, we demonstrate that  d , l -methadone induces leukemic cell apoptosis through activation of the mu1 subtype of opioid receptors (OPRM1).  d , l -Methadone evokes IP3R-mediated ER Ca 2+  release that is inhibited by OPRM1 loss. In addition, the rate of Ca 2+  extrusion following  d , l -methadone treatment is reduced, but is accelerated by loss of OPRM1. These  d , l -methadone effects cause a lethal rise in [Ca 2+ ] i  that is again inhibited by OPRM1 loss, which then prevents  d , l -methadone-induced apoptosis that is associated with activation of calpain-1, truncation of Bid, cytochrome C release, and proteolysis of caspase-3/12. Chelating intracellular Ca 2+  with BAPTA-AM reverses  d , l -methadone-induced apoptosis, establishing a link between the rise in [Ca 2+ ] i  and  d , l -methadone-induced apoptosis. Altogether, our findings point to OPRM1 as a specific target of  d , l -methadone in leukemic cells, and that OPRM1 activation by  d , l -methadone disrupts IP3R-mediated ER Ca 2+  release and rate of Ca 2+  efflux, causing a rise in [Ca 2+ ] i  that upregulates the calpain-1-Bid-cytochrome C-caspase-3/12 apoptotic pathway.

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d,l-Methadone causes leukemic cell apoptosis via an OPRM1-triggered increase in IP3R-mediated ER Ca2+ release and decrease in Ca2+ efflux, elevating [Ca2+]i