Sugar-free approaches to cancer cell killing

Abstract

Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL

“…Removal of glucose or inhibition by 2DG is generally believed to produce essentially the same effects on cellular metabolism and sensitivity to apoptotic agents. 29,43 Our study shows that this is not necessarily true for all cell types. In Z138 cells maintained in glucose-free conditions, TRAIL-R1 and -R2 expression were slightly down-regulated and TRAIL-R1 induced DISC formation and activity (IETDase) attenuated (Figures 3a --d), which could in part explain the slower onset of apoptosis (Figure 4c).…”

Targeting cancer metabolism: a therapeutic window opens

“…Although GLUT1 is expressed at much higher levels in cancer cells than in normal cells it may be difficult to inhibit glucose uptake directly in tumors without an effect on normal tissues. Nevertheless, partial inhibition of glucose uptake may still sensitize cancer cells to other drugs (see 84 for review of various studies). Many of these studies rely on the withdrawal of glucose from cells in culture, illustrating the need for pharmacological agents that inhibit glucose uptake.…”

“…Cells exposed to sufficient amounts of 2DG undergo growth arrest and/or apoptosis 85 , and 2DG may potentiate standard cytotoxic chemotherapy 84,86 . 2DG has been tested as an anti--cancer agent in patients 87 , but when given to glioblastoma patients at doses sufficient to limit glucose metabolism in cancer cells, significant toxicity was observed 88,89 .…”

Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response

“…This observation has led researchers to develop new therapeutic strategies using glycolysis inhibitors such as the nonmetabolizable glucose analog 2-deoxyglucose (2DG) (3). 2DG acts as a competitive inhibitor of glucose transport by sharing the same transporters; it is phosphorylated by hexokinase to form 2DG-6-phosphate, which is not metabolized further in the glycolysis pathway, thereby reducing it.…”