In the 1920s, Otto Warburg, one of the leading biochemists of the 20th
century, uncovered a striking phenotype of cancer cells: their increased dependence on
lactic acid fermentation for energy production compared to that of the normal cells
from which they derived. Warburg viewed this metabolic particularity of cancer cells,
which came to be known as the Warburg effect, as a driving force in carcinogenesis.
This perception suggested a novel path for cancer therapy, a strategy that Warburg
himself proposed and defended with passion to his death. However, for many decades,
both his metabolic theory of cancer and suggested therapeutic approach were
essentially ignored by cancer researchers, who were mostly focused on the genetic
basis of the disease and on the intricacies of the pathways known to promote cellular
proliferation, differentiation and death. Still, thanks to the combined efforts of those
who chose to pursue Warburg’s line of research, experimental evidence supporting and
extending Warburg´s findings on the metabolism of cancer cells accumulated. In the
1980s, 18F-deoxyglucose positron emission tomography (18FDG–PET) was
implemented in the clinic. This metabolic imaging technique, which is based on the
avidity of cancer cells for glucose, represents, to this day, the only successful
exploitation of the Warburg effect for medical purposes. The wide success of
18FDG–PET in the diagnosis and staging of tumors is among the factors most
responsible for renewing interest in the central carbon metabolism of cancer cells. This
renewed interest was further boosted by the discovery of multiple links between central
carbon metabolism and cellular proliferation, differentiation and death and culminated in the recent classification, by Weinberg and Hanahan, of tumor metabolism as an
emerging cancer hallmark. Tremendous research effort is now being devoted into a
more detailed and comprehensive elucidation of the metabolic rewiring that
accompanies neoplastic transformation and, unsurprisingly, targeting the metabolic
peculiarities of tumors has become a hot topic in drug discovery. This chapter
summarizes past and current efforts at targeting the Warburg effect for selective cancer
therapies.
Keywords: Aerobic glycolysis, Central carbon metabolism, Clinical trials,
Diabetes, Emerging cancer hallmark, 18F-Deoxyglucose positron emission
tomography (18FDG–PET), Hypoxia, Ketogenic diet, Metabolic cancer therapies,
Metformin, Pasteur effect, Targeted cancer therapies, Warburg effect.
