Succinate-Directed Approaches for Warburg Effect-Targeted Cancer Management, an Alternative to Current Treatments?

SIMPLE SUMMARY: One hundred years ago, it was discovered that some cancer cells have a different metabolism from normal cells. This alternative metabolism is called the Warburg effect, and instead of using glucose to produce energy through the oxidative pathway, the cancer cells undergoing this effect use fermentation, meaning that they behave just as cells exposed to hypoxia do. Despite the fact that it provides less energy, the advantage of using the Warburg metabolism is that cells produce and/or accumulate large quantities of intermediates that favor cell division and tumor progression. Succinate is one of these intermediates, which is accumulated in larger amounts in the Warburg context and contributes to cancer growth. In this review, succinate’s protumoral characteristics are described, and its target value to develop alternative treatment for cancer is discussed. ABSTRACT: Approximately a century ago, Otto Warburg discovered that cancer cells use a fermentative rather than oxidative metabolism even though the former is more inefficient in terms of energy production per molecule of glucose. Cancer cells increase the use of this fermentative metabolism even in the presence of oxygen, and this process is called aerobic glycolysis or the Warburg effect. This alternative metabolism is mainly characterized by higher glycolytic rates, which allow cancer cells to obtain higher amounts of total ATP, and the production of lactate, but there are also an activation of protumoral signaling pathways and the generation of molecules that favor cancer progression. One of these molecules is succinate, a Krebs cycle intermediate whose concentration is increased in cancer and which is considered an oncometabolite. Several protumoral actions have been associated to succinate and its role in several cancer types has been already described. Despite playing a major role in metabolism and cancer, so far, the potential of succinate as a target in cancer prevention and treatment has remained mostly unexplored, as most previous Warburg-directed anticancer strategies have focused on other intermediates. In this review, we aim to summarize succinate’s protumoral functions and discuss the use of succinate expression regulators as a potential cancer therapy strategy.