Editorial

Sugar free, cancer free?

Serine and glycine are biosynthetically linked, and together provide the essential precursors for the synthesis of proteins, nucleic acids, and lipids that are crucial to cancer cell growth. Moreover, serine/glycine biosynthesis also affects cellular antioxidative capacity, thus supporting tumour homeostasis. A crucial contribution of serine/glycine to cellular metabolism is through the glycine cleavage system, which refuels one-carbon metabolism; a complex cyclic metabolic network based on chemical reactions of folate compounds. The importance of serine/glycine metabolism is further highlighted by genetic and functional evidence indicating that hyperactivation of the serine/glycine biosynthetic pathway drives oncogenesis. Recent developments in our understanding of these pathways provide novel translational opportunities for drug development, dietary intervention, and biomarker identification of human cancers.

Most glucose (and glutamine)-deprivation studies of cancer cell cultures focus on total depletion, and are conducted over at least 24 h. It is difficult to extrapolate findings from such experiments to practical anti-glycolytic treatments, such as with insulin-inhibiting diets (with 10%–50% carbohydrate dietary restriction) or with isolated limb perfusion therapy (which usually lasts about 90 min). The aim of this study was to obtain experimental data on the effect of partial deprivation of d-glucose and l-glutamine (to typical physiological concentrations) during 0 to 6-h exposures of HeLa cells.

HeLa cells were treated for 0 to 6 h with 6 mM d-glucose and 1 mM l-glutamine (normal in vivo conditions), 3 mM d-glucose and 0.5 mM l-glutamine (severe hypoglycemic conditions), and 0 mM d-glucose and 0 mM l-glutamine (“starvation”). Polarization-optical differential interference contrast and phase-contrast light microscopy were employed to investigate morphologic changes.

Reduction of glucose levels from 6 to 3 mM (and glutamine levels from 1 to 0.5 mM) brings about cancer cell survival of 73% after 2-h exposure and 63% after 4-h exposure. Reducing glucose levels from 6 to 0 mM (and glutamine levels from 1 to 0 mM) for 4 h resulted in 53% cell survival.

These data reveal that glucose (and glutamine) deprivation to typical physiological concentrations result in significant cancer cell killing after as little as 2 h. This supports the possibility of combining anti-glycolytic treatment, such as a carbohydrate-restricted diet, with chemotherapeutics for enhanced cancer cell killing.