SOD1 inhibition enhances sorafenib efficacy in HBV-related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS-mediated cell death

J Cell Mol Med. 2024 Jul;28(14):e18533. doi: 10.1111/jcmm.18533.

Abstract

Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV-infected patients due to HBx-related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV-positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV-positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC-mediated suppression of SOD1 further enhances SF sensitivity in HBV-positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC-SF combination could serve as a promising strategy for overcoming SF resistance in HBV-related HCC, potentially optimizing therapy outcomes.

Keywords: Sorafenib resistance; disulfiram; hepatitis B virus; hepatocellular carcinoma; superoxide dismutase.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Carcinoma, Hepatocellular* / virology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Ditiocarb / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Hepatitis B / complications
  • Hepatitis B / drug therapy
  • Hepatitis B / virology
  • Hepatitis B virus* / drug effects
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / virology
  • Mice
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Reactive Oxygen Species* / metabolism
  • Signal Transduction* / drug effects
  • Sorafenib* / pharmacology
  • Sorafenib* / therapeutic use
  • Superoxide Dismutase-1* / genetics
  • Superoxide Dismutase-1* / metabolism
  • TOR Serine-Threonine Kinases* / antagonists & inhibitors
  • TOR Serine-Threonine Kinases* / metabolism
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • Xenograft Model Antitumor Assays

Substances

  • Sorafenib
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-akt
  • Superoxide Dismutase-1
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinases
  • SOD1 protein, human
  • Ditiocarb
  • hepatitis B virus X protein
  • MTOR protein, human
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins