title: Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine.
abstract: Current therapy for acute myeloid leukemia (AML) primarily includes high-dose cytotoxic chemotherapy with or without allogeneic stem cell transplantation. Targeting unique cellular metabolism of cancer cells is a potentially less toxic approach. Monotherapy with mitochondrial inhibitors like metformin have met with limited success since escape mechanisms such as increased glycolytic ATP production, especially in hyperglycemia, can overcome the metabolic blockade. As an alternative strategy for metformin therapy, we hypothesized that the combination of 6-benzylthioinosine (6-BT), a broad-spectrum metabolic inhibitor, and metformin could block this drug resistance mechanism. Metformin treatment alone resulted in significant suppression of ROS and mitochondrial respiration with increased glycolysis accompanied by modest cytotoxicity (10-25%). In contrast, 6-BT monotherapy resulted in inhibition of glucose uptake, decreased glycolysis, and decreased ATP with minimal changes in ROS and mitochondrial respiration. The combination of 6-BT with metformin resulted in significant cytotoxicity (60-70%) in monocytic AML cell lines and was associated with inhibition of FLT3-ITD activated STAT5 and reduced c-Myc and GLUT-1 expression. Therefore, although the anti-tumor and metabolic effects of metformin have been limited by the metabolic reprogramming within cells, the novel combination of 6-BT and metformin targets this bypass mechanism resulting in reduced glycolysis, STAT5 inhibition, and increased cell death.
authors.affiliation: Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: Himalee S
authors.initials: HS
authors.lastname: Sabnis
authors.affiliation: Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: Heath L
authors.initials: HL
authors.lastname: Bradley
authors.affiliation: Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Yu
authors.affiliation: Department of Medicine, Division of Bone Marrow Transplantation, University of Louisville, Louisville, KY, USA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Tse
authors.affiliation: Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: Cheng-Kui
authors.initials: CK
authors.lastname: Qu
authors.affiliation: Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA. Electronic address: Kevin.bunting@emory.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005312:Fetal Blood / Q000166:cytology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D055029:Inverted Repeat Sequences; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008687:Metformin / Q000627:therapeutic use*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000502:physiology
chemical_list: C485108:6-benzylthioinosine; D050799:STAT5 Transcription Factor; D013868:Thioinosine; D008687:Metformin; D051941:fms-Like Tyrosine Kinase 3
keywords: Cancer metabolism; Glycolysis; Leukemia; Metformin; Oxidative phosphorylation