title: Induction of apoptosis in pediatric acute lymphoblastic leukemia (ALL) cells by the therapeutic opioid methadone and effective synergy with Bcl-2 inhibition.
abstract: Although recent decades have seen a significant improvement in the treatment outcome of leukemia in the pediatric population, those who are treated for relapsed disease still face significant morbidity and mortality. However, current salvage regimens are often assembled with agents that have similar mode of activity as the chemotherapeutics used in the initial treatment. Hence, novel therapeutic agents that are capable of distinct and diverse mechanisms of activity in, now resistant, leukemia cells are of great interest. We have investigated the opioid agonist methadone for its anti-leukemic activity, initially reported in studies with cell lines derived from adult patients. Our findings show that, compared to normal cells, methadone has enhanced cytotoxicity against specimens and cell lines established from refractory childhood leukemia. In addition, methadone's activity synergized with that of the anti-Bcl-2 agent ABT-737 and was characterized by the induction of distinct changes in tumor cell mitochondria. Data presented also identify biological correlates and a potential mechanism for methadone activity by its effects on Mcl-1 and other members of the apoptosis cascade. We provide mechanistic data for the therapeutic potential of a family of agents that is largely unexplored for anti-leukemic activity.
authors.affiliation: Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB, Canada.
authors.forename: Anjali
authors.initials: A
authors.lastname: Singh
authors.forename: Aarthi
authors.initials: A
authors.lastname: Jayanthan
authors.forename: Allyson
authors.initials: A
authors.lastname: Farran
authors.forename: Adam N
authors.initials: AN
authors.lastname: Elwi
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Peter
authors.initials: P
authors.lastname: Farran
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008691:Methadone / Q000008:administration & dosage / Q000494:pharmacology*; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000453:epidemiology / Q000473:pathology*; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C501332:ABT-737; D000701:Analgesics, Opioid; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D008691:Methadone