Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options

Abstract

Hepatocellular cancer (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death. Locoregional therapies, including transarterial embolization (TAE: bland embolization), chemoembolization (TACE), and radioembolization, have demonstrated survival benefits when treating patients with unresectable HCC. TAE and TACE occlude the tumor's arterial supply, causing hypoxia and nutritional deprivation and ultimately resulting in tumor necrosis. Embolization blocks the aerobic metabolic pathway. However, tumors, including HCC, use the "Warburg effect" and survive hypoxia from embolization. An adaptation to hypoxia through the Warburg effect, which was first described in 1956, is when the cancer cells switch to glycolysis even in the presence of oxygen. Hence, this is also known as aerobic glycolysis. In this article, the adaptation mechanisms of HCC, including glycolysis, are discussed, and anti-glycolytic treatments, including systemic and locoregional options that have been previously reported or have the potential to be utilized in the treatment of HCC, are reviewed.

Keywords: Warburg effect; antiglycolytic drugs; glycolysis; hepatic artery embolization; hepatocellular carcinoma.

Figure 1

Schematic representation of glycolysis and then the enzyme involved. The antiglycolytic drugs are shown in green and the enzyme or transporter that each drug blocks is demonstrated by the yellow mark. Carbonic anhydrases XII (CA XII) and CAIX regulate the intracellular pH at 7.2–7.4 in order for the glycolytic enzymes to be active. Na-Bicarbonate cotransporter (NBC) and Monocarboxylate transporters (MCT) play a crucial role in pH regulation. GLUT = Glucose transporter; hexokinase = HK; G-6-P1 = Glucose-6 phosphate dehydrogenase; PFK = Phosphofructokinase; GAPDH = glyceraldehyde phosphate dehydrogenase; PGK = phosphoglycerate kinase; PGM = phosphoglycerate mutase; PDK = pyruvate dehydrogenase kinase; LDH = Lactate dehydrogenase; 2-DG = 2-deoxy-D-glucose; DCA = Dichloroacetate; TCA = Tricarboxylic acid.