Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

Abstract

Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called "Warburg effect". Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.

Keywords: 3-bromopyruvate; aerobic glycolysis; antitumor effect; glycolytic inhibitor; tumor energy metabolism.

Figure 1

The energy metabolism of normal differentiated tissues and tumor or proliferating tissues. (A) In normal differentiated tissues, under aerobic condition, a molecule of glucose is first converted to two pyruvates via glycolysis in the cytosol, followed by undergoing TCA cycle to produce CO₂ in the mitochondria. A total of 30 or 32 ATP molecules are generated during this process. Under anaerobic condition, glycolysis is preferential and less pyruvate is shifted to the oxygen-consuming mitochondria, only 2 ATP molecules are produced per molecule of glucose. (B) In tumor or proliferating tissues, mitochondrial function is still normal, but little mitochondrial oxidative phosphorylation (OXPHOS) continues in tumor cells. In order to satisfy the metabolic requirements of both energy and materials for rapidly proliferating cells, ~85% of the glucose is processed to lactate via glycolytic pyruvate even in the presence of oxygen and ~5% of the glucose is metabolized by OXPHOS. In addition, ~10% of the glucose is diverted into the upstream of pyruvate production for biosynthesis (e.g., pentose phosphate pathway, PPP).

Figure 2

Schematic representation of metabolism in tumor cells. Mutation-mediated continuous activation of PI3K/AKT signaling pathway upregulates the expression of glucose transporters (GLUTs) and substantially enhances the capture of glucose into the cytoplasm by HK, and activates PFK or upregulates PFK expression, leading to the high rate of glucose influx, which in turn facilitates the aerobic glycolysis. The glycolytic switch in tumor cells allows the direct or indirect flux of glycolytic intermediates to many biosynthetic pathways (e.g., PPP, amino acid synthesis, lipid synthesis, and nucleotide synthesis), which provides the biomacromolecules and other materials required for producing new daughter cells. In addition, the intermediates of glutaminolysis are also used for synthesizing biomass that rapidly growing tumor cells need.

Figure 3

Schematic representation of tumor imaging by ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) technology.

Figure 4

Structure, decomposition, and mechanism of action of 3-BrPA. (A) Proposed mechanism of decomposition in solutions with different pH values. (B) Modification or inactivation of proteins, enzymes, or glutathione by 3-BrPA through the covalent binding of a pyruvic moiety to the thiol groups (especially the –SH group) of targets.

Figure 5

Underlying mechanism of 3-BrPA-mediated antitumor activity. 3-BrPA enters tumor cells via tumor-specific overexpression of monocarboxylate transporters (MCTs) (especially MCT1), followed by the inhibition of glycolysis (e.g., HK-II, GAPDH, and 3-PGK), mitochondrial OXPHOS (e.g., PDH, SDH, IDH, and αKD), PPP (e.g., G6PDH), glutaminolysis (e.g., IDH and αKD), the MG pathway (e.g., glyoxylase I and II), HDACs, and H⁺-vacuolar ATPase, downregulation of G6PDH and direct conjugation with GSH, leading to the decrease of intracellular ATP, an increase in oxidative stress (e.g., ROS), inhibition of anabolic process (e.g., PPP), carbonyl stress (e.g., MG), and destabilization of liposome. Consequentially, 3-BrPA selectively induces cell death by apoptosis or necrosis, while normal cell remains unaffected.

Figure 6

Stable liposomal nanoparticle formulation for selectively delivering 3-BrPA to tumors.