Glucose Starvation Induces Apoptosis in a Model of Acute T Leukemia Dependent on Caspase-3 and Apoptosis-Inducing Factor: A Therapeutic Strategy

Abstract

Reactivation of apoptosis appears as an ultimate goal to eliminate cancer cells. By using light and fluorescent microscopy, flow cytometry, immunohistochemistry staining, DNA fragmentation analysis, and pharmacological inhibition, we provide evidence that 2 pathways of cell death induced by glucose-starvation (GS)/oxidative stress (OS) run in parallel: apoptosis-inducing factor (AIF)-dependent and caspase-3 dependent mechanisms. However, the supremacy of 1 pathway over the other one relies on the availability of glucose, which is essential for the proper functioning of antioxidant cellular systems. It is shown that GS generates superoxide anion radical (O₂ ⁻)/hydrogen peroxide (H₂O₂), which are linked to the death ∼45%–70% cells by AIF/mitochondria depolarization/chromatin condensation pathway and ∼15%–30% death by nuclear factor-kappa B/p53/c-Jun/c-Jun N-terminal kinase /mitochondria depolarization/caspase-3 activation/DNA fragmentation mechanism at 24–48 h. Remarkably, chromatin condensation/nuclei fragmentation appeared to occur partially independent of the loss of the mitochondrial transmembrane potential (ΔΨ_m) and plasma membrane damage. Interestingly, signaling inhibitors, antioxidants, or glucose protected cells if added immediately to culture devoid of glucose (P < 0.001), but only vitamin E and glucose significantly rescued cells at 3 h of GS compared to control. Taken together these data suggest that glucose deprivation might efficiently eliminate leukemia cells via apoptosis.

ACKNOWLEDGMENTS

This work was supported by Colciencias grants #1115-408-20525 and #1115-343-19119 to Carlos Velez-Pardo and Marlene Jimenez-Del-Rio. Miguel Mendivil-Perez is associated researcher founded by Colciencias contract #8790-2514-2010 and founded from a Young Research Program Award by Colciencias contract #8790-016-2011. We thank Catalina Burbano-Arciniegas from the Flow Cytometry Unit, GICIG-SIU-UdeA for technical assistance.