Review

Oncogene (2011) 30, 253–264; doi:10.1038/onc.2010.466; published online 25 October 2010

Sugar-free approaches to cancer cell killing

N El Mjiyad1,2, A Caro-Maldonado1,2, S Ramírez-Peinado1 and C Muñoz-Pinedo1

1Cell Death Regulation Group, IDIBELL (Bellvitge Biomedical Research Institute), L’Hospitalet de Llobregat, Barcelona, Spain

Correspondence: Dr C Muñoz-Pinedo, Molecular Oncology, IDIBELL, Hospital Duran i Reynals 3a planta, Gran Vía de L’Hospitalet 199, L’Hospitalet, Barcelona 08907, Spain. E-mails: cmunoz@idibell.cat or munozpinedo@gmail.com

2These authors contributed equally to this work.

Received 11 July 2010; Revised 3 September 2010; Accepted 3 September 2010; Published online 25 October 2010.

Top

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.

Keywords:

cancer; apoptosis; glucose; tumor metabolism; Bcl-2 proteins