The accelerated metabolism of
tumor cells, inevitable for maintaining high proliferation rates, is an emerging target for
tumor therapy. Increased
glucose and lipid metabolism as well as mitochondrial activity have been shown in solid
tumors but also in leukemic cells. As
tumor cells are able to escape the blockade of one metabolic pathway by a compensatory increase in other pathways, treatment strategies simultaneously targeting metabolism at different sites are currently developed. However, the number of clinically applicable anti-metabolic drugs is still limited. Here, we analyzed the impact of the anti-diabetic drug
metformin alone or in combination with two non-steroidal anti-inflammatory drugs (
NSAIDs)
diclofenac and
diflunisal on
acute myeloid leukemia (AML) cell lines and primary patient blasts.
Diclofenac but not
diflunisal reduced
lactate secretion in different AML cell lines (THP-1, U937, and KG-1) and both drugs increased respiration at low concentrations. Despite these metabolic effects, both
NSAIDs showed a limited effect on
tumor cell proliferation and viability up to a concentration of 0.2 mM. In higher concentrations of 0.4-0.8 mM
diflunisal alone exerted a clear effect on proliferation of AML cell lines and blocked respiration. Single treatment with the anti-diabetic drug
metformin blocked mitochondrial respiration, but proliferation and viability were not affected. However, combining all three drugs exerted a strong
cytostatic and cytotoxic effect on THP-1 cells. Comparable to the results obtained with THP-1 cells, the combination of all three drugs significantly reduced proliferation of primary leukemic blasts and induced apoptosis. Furthermore,
NSAIDs supported the effect of low dose
chemotherapy with
cytarabine and reduced proliferation of primary AML blasts. Taken together we show that low concentrations of
metformin and the two
NSAIDs diclofenac and
diflunisal exert a synergistic inhibitory effect on AML proliferation and induce apoptosis most likely by blocking
tumor cell metabolism. Our results underline the feasibility of applying anti-metabolic drugs for AML
therapy.