Possible Link between Glycolysis and Apoptosis Induced by Sodium Fluoride

Abstract

Fluoride has been used to prevent caries in the dentition, but the possible underlying mechanisms of cytotoxicity induction by this compound are still unclear. Since fluoride is known as an inhibitor of glycolytic enzymes, we investigated the possible connection between NaF-induced apoptosis and glycolysis in human promyelocytic leukemia HL-60 cells. NaF-induced apoptotic cell death is characterized by caspase activation, internucleosomal DNA fragmentation, loss of mitochondrial membrane potential, and production of apoptotic bodies. Higher activation of caspases-3 and -9, as compared with that of caspase-8, suggested the involvement of an extrinsic pathway. Utilization of glucose was nearly halted by NaF, whereas that of glutamine was rather enhanced. NaF enhanced the expression of Bad protein, but not that of Bcl-2 and Bax proteins, and reduced HIF-1alpha mRNA expression. Analysis of these data suggests a possible link between glycolysis and apoptosis.

2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition

“…However, 3-BrPA failed to induce Akt phosphorylation in HeLa cells, suggesting that the inhibition of hexokinase or the depletion of intracellular ATP concentration is not related to 2-DG-induced Akt phosphorylation. We also targeted other enzymes in the glycolytic pathways by inhibiting 6-phospho-D-gluconate:NADP oxidoreductase (6-PG dehydrogenase) with 6-aminonicotinamide (36), pyruvate dehydrogenase with arsenic (37), lactate dehydrogenase with sodium oxamate (38), transketolase-like-1 with oxythiamine, and enolase with sodium fluoride (39), yet most of them did not induce Akt phosphorylation, suggesting that the inhibition of glycolysis is not linked to Akt activation.…”

Molecular Mechanisms of Cytotoxicity and Apoptosis Induced by Inorganic Fluoride

“…Thus, an exposure of the human promyelocytic HL-60 cells to 2-5 mM NaF led to significant increase in the level of cytosolic cytochrome c, activation of caspase-3, and subsequent cleavage of intact PARP leading to DNA damage [45,46,129]. In the same cells, Otsuki et al [47] reported an increased activity of caspase-9. The similar activation of caspase-3, cleavage of PARP, and DNA fragmentation were observed in the MDPC-23 odontoblast-like cells exposed to 5mM NaF [21].…”

“…Many of these cellular events ultimately lead to cell death. NaFinduced apoptosis was demonstrated in the cells from different organs and tissues including lungs [25,26], kidneys [27,28], liver [29][30][31], brain [32][33][34], pancreas [35,36], thymus [37], endometrium [38,39], bone marrow [40], hair follicles [41], erythrocytes [42][43][44], as well as leukemic cells [45][46][47].…”

“…Although this effect is known since 40 years of the twentieth century, it is often underestimated or ignored in the studies of fluoride cytotoxicity and cell death. A few works reported the significant (70-90%) decrease in ATP content in the human [123] and rat (Agalakova and Gusev, unpublished data) erythrocytes, oral mucosal fibroblasts [124], and macrophages [103] in in vitro studies; however, the direct link between NaF-induced inhibition of glycolysis and apoptosis was established only in the HL-60 cells exposed to 7.5-20 mM NaF [47]. Since energy supply is a limiting factor in a variety of biochemical processes, ATP depletion can arrest many crucial cellular functions like transmembrane ion transport and protein phosphorylation, disturb membrane potential, and membrane-cytoskeleton interactions, what may finally lead to cell death [17,50].…”

Effect of Cu2+ ion on Biological Performance of Nanostructured Fluorapatite Doped with Copper

“…For instance, uoride has shown considerably higher cytotoxicity against tumor cell lines than normal cells [36]. Besides, in this study, just high concentration of the prepared samples is investigated which may result in di erent observation than concentrations lower than 1% of sample test.…”