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.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B virus , Liver Neoplasms , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Reactive Oxygen Species , Signal Transduction , Sorafenib , Superoxide Dismutase-1 , TOR Serine-Threonine Kinases , Sorafenib/pharmacology , Sorafenib/therapeutic use , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/virology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/virology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Reactive Oxygen Species/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Superoxide Dismutase-1/metabolism , Superoxide Dismutase-1/genetics , Animals , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/drug effects , Mice , Hepatitis B virus/drug effects , Cell Line, Tumor , Xenograft Model Antitumor Assays , Apoptosis/drug effects , Hepatitis B/complications , Hepatitis B/drug therapy , Hepatitis B/virology , Ditiocarb/pharmacology , Drug Resistance, Neoplasm/drug effects , Mice, Nude , Cell Proliferation/drug effects , Trans-Activators , Viral Regulatory and Accessory ProteinsABSTRACT
In the liver, reactive oxygen species (ROS) are constantly released during cellular metabolic processes, and excess ROS production can cause redox stress. The redox stress is both beneficial for and harmful to the survival of cells since it modulates the cellular redox control system. The redox control system is a series of cellular responses that are responsible for maintaining a balanced oxidation-reduction status. Many cellular processes including growth, proliferation, and senescence are sensitively regulated by the redox control system. Imbalance of redox induces redox stress and damages DNA, proteins, and lipids in cells, and further contributes to the pathogenesis of severe diseases and disorders like cancer. However, the cellular redox control system also utilizes redox stress-responsive pathways and increases antioxidant enzymes to aid cell survival. Therefore, a deeper understanding of the connection between the redox control system and liver disease is likely to pave the way for the future development of new therapeutic strategies. This review will examine the redox control systems in liver with responsive regulating molecules, current knowledge of the redox control system and liver disease, and suggest potential therapeutic targets for liver diseases.
Subject(s)
Liver Diseases , Oxidative Stress , Humans , Reactive Oxygen Species/metabolism , Oxidation-Reduction , Liver Diseases/drug therapy , Antioxidants/therapeutic use , Antioxidants/metabolismABSTRACT
This study aimed to establish and reproduce transgenic pigs expressing human growth hormone (hGH) in their milk. We also aimed to purify hGH from the milk, to characterize the purified protein, and to assess the potential of our model for mass production of therapeutic proteins using transgenic techniques. Using ~15.5 L transgenic pig milk, we obtained proteins with ≥ 99% purity after three pre-treatments and five column chromatography steps. To confirm the biosimilarity of our milk-derived purified recombinant hGH (CGH942) with commercially available somatropin (Genotropin), we performed spectroscopy, structural, and biological analyses. We observed no difference between the purified protein and Genotropin samples. Furthermore, rat models were used to assess growth promotion potential. Our results indicate that CGH942 promotes growth, by increasing bone development and body weight. Toxicity assessments revealed no abnormal findings after 4 weeks of continuous administration and 2 weeks of recovery. The no-observed-adverse-effect level for both males and females was determined to be 0.6 mg/kg/day. Thus, no toxicological differences were observed between commercially available somatropin and CGH942 obtained from transgenic pig milk. In conclusion, we describe a transgenic technique using pigs, providing a new platform to produce human therapeutic proteins.