Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

Abstract

Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease (CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma.

Keywords: Hepatitis B; Hepatitis C; Liver cancer; Liver cirrhosis; Non-alcoholic steatohepatitis; Reactive oxygen species.

Figure 1

Oxidative stress production and treatment targets in hepatocytes. High levels of plasma free fatty acids increase levels of hepatic free fatty acids. Long-chain fatty acids taken up by mitochondria as complexes with L-carnitine are subsequently metabolized in β-oxidation pathway. Under oxidative stress, oxidative reactions convert oxidized cofactors (NAD⁺ and FAD) into reduced cofactors (NADH and FADH2) and deliver electrons to respiratory chain. Imbalance between increased delivery of electrons to, and decreased outflow from respiratory chain causes electrons and ROS products to accumulate. Antioxidant defenses, such as superoxide dismutase (SOD), glutathione peroxidase (GPx) or catalase can metabolize O₂^- and H₂O₂ to non-toxic H₂O. However, Fenton and/or Haber-Weiss reactions generate highly reactive, toxic, hydroxyl radicals (•OH). Vitamin E and hydrogen as general and selective cytotoxic ROS scavengers erase oxidative stress. L-carnitine supports mitochondrial function to increase long-chain fatty acid uptake. Metformin or thienopyridone activates AMPK and induces antioxidant gene transcription and AICAR activates Nrf2, possibly like metformin. AICAR: 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside; AMPK: AMP-activated protein kinase; Keap1: Kelch-like ECH associating protein; Nrf2: Nuclear factor erythroid 2-related factor.