Deciphering enemy tactics – the narrow path to an optimal anti-cancer strategy targeting the Warburg effect

Metabolic changes in cancer cells are crucial for maintaining their high growth and proliferation rate. As a result, many tumors are characterized by high glucose consumption and intensified aerobic glycolysis, a phenomenon known as the Warburg effect. Through the Warburg effect, cancer cells can rapidly acquire energy, obtain intermediates for biosynthesis, and ensure a source of NAD+ for oxidized biomass synthesis. Altered metabolism and the Warburg effect are characteristic features not only of most transformed proliferating cells but also of normal, rapidly dividing cells, thus posing a challenge for potential anticancer strategies disrupting cellular metabolism. Therefore, targeting the Warburg effect requires a carefully considered strategy so as not to affect the basal metabolism of normal cells and prevent the various side effects in the patient commonly observed with classical chemotherapies targeting DNA replication. On the other hand, strategies/agents that slow metabolic rate are likely to be less toxic to normal cells than to highly metabolically deregulated cancer cells. The aim of this work is to discuss the most optimal approach for inhibiting these favorable metabolic changes in cancer cells while ensuring specificity. The work discusses proteins, enzymes and pathways that, according to the current state of knowledge, can be optimal candidates for cancer specific targeting such as: HK2, PKM2, PFKFB3, PFKFB4, NAD+ de novo metabolism, NADH oxidation, MCT4, MCT1, LDHA and LDHB. In the era of rapid progress in diagnostic tools providing more and more data on molecular changes, the therapeutic strategy should take into account not only the specificity of the cancer, but also a personalized, optimal approach for each individual patient. This article presents an overview, including available databases, showing the heterogeneity of expression of genes involved in metabolic reprogramming among various cancer patients, which clearly suggests the need to develop a specific theranostic approach for targeting the Warburg effect in a personalized manner. Clinical trial number Not applicable.