Fatty acid synthesis and oxidation are frequently exacerbated in
leukemia cells, and may therefore represent a target for therapeutic intervention. In this work we analyzed the apoptotic and chemo-sensitizing action of the
fatty acid oxidation inhibitor
etomoxir in human
acute myeloid leukemia cells.
Etomoxir caused negligible lethality at concentrations up to 100 µM, but efficaciously cooperated to cause apoptosis with the anti-leukemic agent
arsenic trioxide (ATO,
Trisenox), and with lower efficacy with other anti-tumour drugs (
etoposide,
cisplatin), in HL60 cells.
Etomoxir-ATO cooperation was also observed in NB4 human acute promyelocytic cells, but not in normal (non-tumour)
mitogen-stimulated human peripheral blood lymphocytes. Biochemical determinations in HL60 cells indicated that
etomoxir (25-200 µM) dose-dependently inhibited mitochondrial respiration while slightly stimulating glycolysis, and only caused marginal alterations in total
ATP content and
adenine nucleotide pool distribution. In addition,
etomoxir caused oxidative stress (increase in intracellular
reactive oxygen species accumulation, decrease in
reduced glutathione content), as well as pro-apoptotic LKB-1/AMPK pathway activation, all of which may in part explain the chemo-sensitizing capacity of the
drug.
Etomoxir also cooperated with glycolytic inhibitors (2-deoxy-D-glucose, lonidamine) to induce apoptosis in HL60 cells, but not in NB4 cells. The combined
etomoxir plus
2-deoxy-D-glucose treatment did not increase oxidative stress, caused moderate decrease in net
ATP content, increased the
AMP/
ATP ratio with concomitant drop in energy charge, and caused defensive Akt and ERK
kinase activation. Apoptosis generation by
etomoxir plus
2-deoxy-D-glucose was further increased by co-incubation with ATO, which is apparently explained by the capacity of ATO to attenuate Akt and ERK activation. In summary, co-treatment with
etomoxir may represent an interesting strategy to increase the apoptotic efficacy of ATO and (with some limitations)
2-deoxy-D-glucose which, although clinically important anti-tumour agents, exhibit low efficacy in monotherapy.