Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy

Abstract

In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy

“…Typically, in a CR or dietary restriction regimen, carbohydrates (the main source of energy in the regular diet) are reduced and replaced partially or nearly completely (as in the ketogenic diet) by fat [16]. Indeed, reducing sugar intake seems to be a good strategy to fight cancer, given that cancer cells use glucose as the main fuel [17,18]. Likewise providing ketones as alternative energy source may limit cancer growth because cancer cells do not efficiently harness ketones for their anabolism [19,20].…”

A suppressor of dioxygenase inhibition in a yeast model of SDH deficiency

“…The disease consequences of metabolic perturbation are of central importance in medicine. Metabolic changes in cancer have been detected and discussed since the discovery of the Warburg effect ( Warburg 1956 , Pavlova & Thompson 2016 , de Alteriis et al 2018 , Kozal et al 2021 ). SDH-loss familial PGL presents a unique metabolic state with its fragmented TCA cycle.…”

“…Cancer was characterized by a metabolic perturbation now known as the Warburg effect, the observation that cancer cells exhibit glycolytic, rather than oxidative, metabolism even when oxygen is abundant ( Warburg 1956 ). Since this discovery, many cancers have been found to have other forms of altered metabolism besides the Warburg effect ( Pavlova & Thompson 2016 , Kozal et al 2021 ). Familial paraganglioma (PGL) is a remarkable example.…”

A chemical screen for suppressors of dioxygenase inhibition in a yeast model of familial paraganglioma

“…Metabolic changes in cancer have been detected and discussed since the discovery of the Warburg Effect (de Alteriis et al, 2018;Kozal et al, 2021;Pavlova and Thompson, 2016;Warburg, 1956).…”

“…Cancer was characterized by a metabolic perturbation now known as the Warburg Effect, the observation that cancer cells exhibit glycolytic, rather than oxidative, metabolism even when oxygen is abundant (Warburg, 1956). Since this discovery, many cancers have been found to have other forms of altered metabolism besides the Warburg effect (Kozal et al, 2021;Pavlova and Thompson, 2016). Familial paraganglioma (PGL) is a remarkable example.…”