Glucose starvation induces apoptosis in a model of acute T leukemia dependent on caspase-3 and apoptosis-inducing factor: a therapeutic strategy.
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 (O(2)(-))/hydrogen peroxide (H(2)O(2)), 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.
School of Medicine, Medical Research Institute, University of Antioquia, Medellin, Colombia.
Miguel
M
Mendivil-Perez
Marlene
M
Jimenez-Del-Rio
Carlos
C
Velez-Pardo
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D053938:DNA Fragmentation; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial; D016328:NF-kappa B / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
C494829:AIFM1 protein, human; D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D002843:Chromatin; D016328:NF-kappa B; D013481:Superoxides; D014810:Vitamin E; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D005947:Glucose