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Metformin suppresses pediatric AML cell viability and prolongs survival in a relapse
model of leukemia
Barwe S. P. 1, Bollinger E. 1, Balasubramaniam S. 1, Kolb E. A. 1, Gopalakrishnapillai A. 1
1
Alfred I. duPont Hospital for Children, Wilmington, DE 19803
[email protected]
Background and Objective: Acute myeloid leukemia (AML) accounts for 15-20% of childhood
leukemia. 30-40% of the patients face disease relapse. Therapies that could sustain the
remission phase in pediatric AML are urgently needed. Metformin is a non-toxic anti-diabetic
drug with some anti-cancer effect. Therefore, we tested the effect of metformin in pediatric AML
in vitro and in vivo.
Methods: Cell viability and clonogenicity was assayed using Cell Titer Blue and methyl cellulose
colony formation assay respectively. Mitochondrial morphology was determined by transmission
electron microscopy. Phosphoprotein array and immunoblotting was performed to identify
signaling pathways modulated by metformin. Leukemia relapse model was generated by
transplantation of AML cells in immune-deficient mice.
Results: Metformin decreased the viability and clonogenicity of AML cell lines in a dosedependent manner. This effect was independent of AMPK activation. Phosphoprotein array
analysis suggests a role for STAT3 S727 in the mechanism of metformin-induced cytotoxicity. A
transmission electron micrograph showed differences in mitochondrial morphology in metforminresistant cells. Remission phase was prolonged by metformin treatment in a leukemia relapse
mouse model.
Discussion and Conclusions: AMPK activation by metformin is cell-type specific and is not
required for metformin-mediated AML cell death. Metformin reduced clonogenic potential and
showed efficacy in prolonging remission in a leukemia relapse mouse model.
Acknowledgement: This work was supported by Delaware INBRE, NIH-NIGMS (P20
GM103446).