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D,L-Methadone causes leukemic cell apoptosis via an OPRM1-triggered increase in IP3R-mediated ER Ca2+ release and

JungKwon Lee1,2, Jesusa L Rosales1, Hee-Guk Byun2

  • 1Department of Cell Biology and Anatomy, Arnie Charbonneau Cancer, Alberta Children's Hospital Research Institutes, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.

Scientific Reports
|January 14, 2021
PubMed

Insights

D,L-methadone induces apoptosis in acute lymphoblastic leukemia (aLL) cells by activating mu1 opioid receptors (OPRM1). This mechanism involves calcium release and disruption of calcium extrusion, leading to cell death via the calpain-1 pathway.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Acute lymphoblastic leukemia (aLL) remains a significant pediatric malignancy requiring novel therapeutic strategies.
  • D,L-methadone has emerged as a potential sensitizer for aLL chemotherapy, but its cellular targets and mechanisms of action are not fully understood.

Purpose of the Study:

  • To elucidate the specific molecular target and mechanism by which D,L-methadone induces apoptosis in aLL cells.
  • To investigate the role of opioid receptors and intracellular calcium signaling in D,L-methadone's anti-leukemic effects.

Main Methods:

  • Investigated D,L-methadone's effects on aLL cell apoptosis.
  • Utilized OPRM1 knockout models to assess receptor dependency.
  • Monitored intracellular calcium ([Ca2+]i) dynamics, including ER Ca2+ release and Ca2+ extrusion.
  • Analyzed key proteins in the apoptotic cascade (calpain-1, Bid, cytochrome C, caspase-3/12).

Main Results:

  • D,L-methadone-induced apoptosis is mediated by the activation of the mu1 subtype of opioid receptors (OPRM1).
  • D,L-methadone disrupts inositol trisphosphate receptor (IP3R)-mediated ER Ca2+ release and reduces Ca2+ extrusion rates.
  • These calcium dysregulations lead to a lethal rise in intracellular calcium, activating the calpain-1/Bid/cytochrome C/caspase-3/12 apoptotic pathway.

Conclusions:

  • OPRM1 is identified as a specific target of D,L-methadone in aLL cells.
  • D,L-methadone's pro-apoptotic effects are dependent on OPRM1 activation and subsequent intracellular calcium overload.
  • These findings provide a mechanistic basis for D,L-methadone as a potential sensitizer in aLL therapy.

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