Almost a century ago, Otto Warburg, MD, PhD, demonstrated that cancer cells prefer to obtain energy via glycolysis, taking in large amounts of glucose and producing lactic acid at high levels, even in the presence of oxygen and healthy mitochondria.1
The process through which cancer cells generate energy, however, differs from that of healthy cells. Normal, healthy cells produce adenosine triphosphate (ATP), which transports energy for metabolism, mainly though oxidative phosphorylation. Cancer cells exhibit a propensity for using aerobic glycolysis to produce ATP over the more efficient oxidative phosphorylation process. This preference, termed the Warburg effect, has since been observed in many tumor types and has emerged as one of the hallmarks of cancer (Figure 1
Figure 1. Differences in the Process of Glycolysis
Despite its importance, the mechanisms behind the Warburg effect are not well understood. Nevertheless, due to its presence in a wide range of cancers, the Warburg effect has become an intriguing target for anticancer therapeutics. Although most antitumor therapies are designed to treat a specific cancer type, therapeutics that target the Warburg effect have the potential to treat a broad range of cancers.
Drug development efforts have aimed at exploiting the aberrant metabolic processes of cancer cells by interfering with energy generation and metabolite production, but this strategy has been challenging. Recently, however, the combination therapy SM-88, which works through the Warburg effect, has been showing promise in prostate and other cancers.
The development of these types of therapies has the potential to provide broad-range treatment with minimal adverse effects, leading to better patient care and favorable outcomes.
The Warburg Effect and Cancer Metabolism
Glycolysis is a stage of cellular respiration through which glucose is converted into growth and survival.6
It has since been established that malignant cells reprogram their metabolic pathways to support uncontrolled cell growth, maintaining oxidative phosphorylation processes while ramping up glycolysis. Several hypotheses exist to explain the pyruvate to release energy in the form of ATP. Although aerobic glycolysis is less efficient than oxidative phosphorylation, producing fewer molecules of ATP per unit of glucose, malignant cells may favor it because the process can be executed significantly faster.3
Cancer cells that favor glycolysis can quickly generate energy by increasing glucose uptake. Increased uptake results in an increase in glycolytic rate, facilitating the generation of ATP that can meet the demands of uncontrolled cell growth.
Initially, cells that exhibited the Warburg effect were hypothesized to have defective mitochondrial metabolism, but this theory has since been disproved.4,5
Most cancer cells not only have functioning mitochondria, but mitochondrial respiration is required for tumor growth and survival.6
It has since been established that malignant cells reprogram their metabolic pathways to support uncontrolled cell growth, maintaining oxidative phosphorylation processes while ramping up glycolysis.
Several hypotheses exist to explain malignant cell’s preference for glycolysis.7
In addition to generating ATP, the carbon sources obtained from the increase in glucose flux fuel the demands for the synthesis of building blocks like amino acids, nucleotides, and lipids.8
Although these metabolic alterations are a well-established cancer phenomenon, the signals that mediate the Warburg effect initiation and persistence remain unclear.7
In addition to increasing the supply of ATP and carbon, the production and export of high levels of lactate acidify the tumor microenvironment.9
Such an acidic environment is toxic to normal, healthy cells and can even inactivate therapeutics, but malignant cells thrive. The acidic microenvironment also appears to enhance tumor cell invasion.10
The Warburg effect also disrupts reactive oxygen species (ROS) signaling. By converting pyruvate into lactate in excess, malignant cells generate a surplus of the coenzyme NAD+, altering the redox balance of the cell. In addition, fewer ROS are produced by cells exhibiting the Warburg effect, insulating themselves from oxidative stress–induced damage and apoptosis.11,12
Cancer cells also upregulate the expression of transmembrane mucin proteins to protect themselves from ROS.13,14
Mucins, particularly MUC1, regulate ROS levels by upregulating antioxidant enzymes. As a result, malignant cells are protected from self-imposed toxicity.