Abstract
This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the “Warburg” and “Crabtree” effects. This work also summarizes two key discoveries, one of which relates to hexokinase-2 (HK2), a major player in both the “Warburg effect” and cancer cell immortalization. The second discovery relates to the finding that cancer cells, unlike normal cells, derive as much as 60% of their ATP from glycolysis via the “Warburg effect”, and the remaining 40% is derived from mitochondrial oxidative phosphorylation. Also described are selected anticancer agents which generally act as strong energy blockers inside cancer cells. Among them, much attention has focused on 3-bromopyruvate (3BP). This small alkylating compound targets both the “Warburg effect”, i.e., elevated glycolysis even in the presence oxygen, as well as mitochondrial oxidative phosphorylation in cancer cells. Normal cells remain unharmed. 3BP rapidly kills cancer cells growing in tissue culture, eradicates tumors in animals, and prevents metastasis. In addition, properly formulated 3BP shows promise also as an effective anti-liver cancer agent in humans and is effective also toward cancers known as “multiple myeloma”. Finally, 3BP has been shown to significantly extend the life of a human patient for which no other options were available. Thus, it can be stated that 3BP is a very promising new anti-cancer agent in the process of undergoing clinical development.
Highlights
The “Warburg Effect” is cancers’ oldest known hallmark, i.e., aberrant sugar metabolism to lactic acid even in the presence of oxygen
Following the subsequent discovery 18 years later that mitochondria are the site of ATP synthesis by oxidative phosphorylation [2,3], Warburg assumed that the high aerobic glycolysis that he and colleagues had observed previously in many cancers resulted from the lowered capacity of mitochondria to utilize oxygen, and may be a putative cause of cancer [4]
About 90% of the ATP is derived from mitochondrial oxidative phosphorylation, and only about 10% comes from the metabolism of glucose to pyruvic acid
Summary
The “Warburg Effect” is cancers’ oldest known hallmark, i.e., aberrant sugar (glucose) metabolism to lactic acid even in the presence of oxygen. Cells from most cancers, regardless of the tissue of origin, exhibit a very intense sugar (glucose) consumption which may exceed 10-fold that of normal cells [1]. This results in an elevated production and extrusion of lactic acid even in the presence of oxygen [1]. Following the subsequent discovery 18 years later that mitochondria are the site of ATP synthesis by oxidative phosphorylation [2,3], Warburg assumed that the high aerobic glycolysis that he and colleagues had observed previously in many cancers resulted from the lowered capacity of mitochondria to utilize oxygen, and may be a putative cause of cancer [4]. Neither assumption was completely correct nor incorrect, there was much more to be learned as will be noted below as this brief review develops
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