Figure 1. D,L-Methadone and signaling pathways. D,L-Methadone (Methadone) sensitizes tumor cells to anticancer therapy and induces apoptosis via activation of opioid receptor signaling pathways. Triggering opioid receptors (OR) using D,Lmethadone leads to down-regulation of cyclic adenosine monophosphate (cAMP) which further down-regulates the anti-apoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and B-cell lymphoma-extra large (BCL-XL) and activates caspase-9 and caspase-3, cleaving poly (ADP-ribose) polymerase (PARP), inducing apoptosis. Blocking opioid receptor signaling pathways using naloxone, 3-isobutyl-1-methylxanthine (IBMX) or pertussis toxin (PTX) inhibits D,L-methadone, sensitizing tumor cells to anticancer treatment and blocks D,L-methadone-related apoptosis induction. AC: Adenylylcyclase, APAF-1: apoptosis protease activating factor-1, AMP: adenosine monophosphate, ATP: adenosine triphosphate, BAX: BCL-2-associated X protein, cyt C: cytochrome c, G: G proteins (Gα, Gβ/Gγ subunits), OR: opioid receptor, PDE: phosphodiesterase.