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Author Notes:

Address correspondence to: Kevin D. Bunting, Ph.D., Department of Pediatrics, Division of Hem/Onc/BMT, Aflac Cancer and Blood Disorders Center, Emory University, 1760 Haygood Dr. NE, HSRB E308, Atlanta, GA 30322, Tel: 404-778-4039, Kevin.bunting@emory.edu.

We are also grateful to the Emory + Children’s Department of Pediatrics Flow Cytometry core facility.

We thank Gang Huang (Cincinnati Children’s Hospital) for generously providing AML cell lines and the Duke Cord Blood Center for providing normal human umbilical cord blood.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors have no conflicts of interest to disclose.

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Research Funding:

This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454 and ACTSI KL2 Award number TR000455 (H.S. Sabnis), the Rally Foundation for Childhood Cancer Research (K.D. Bunting), the Cure Childhood Cancer Foundation (K.D. Bunting), and Children’s Healthcare of Atlanta (K.D. Bunting).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Hematology
  • Metformin
  • Cancer metabolism
  • Oxidative phosphorylation
  • Glycolysis
  • Leukemiaa
  • C-MYC
  • AML

Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine


Journal Title:

Leukemia Research


Volume 50


, Pages 132-140

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2016 Elsevier Ltd. All rights reserved.

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