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

Autor: Lee J; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of Biochemistry and Molecular Biology, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Kim J; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of Biochemistry and Molecular Biology, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Lee R; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of Biochemistry and Molecular Biology, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Lee E; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of Biochemistry and Molecular Biology, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., An HI; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of Biochemistry and Molecular Biology, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Kwon YJ; Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Seoul, South Korea., Jin H; Division of Vascular Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Pack CG; Convergence Medicine Research Center (CREDIT), Asan Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea., Kim I; Convergence Medicine Research Center (CREDIT), Asan Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea., Yoon YI; Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Park GC; Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Jwa EK; Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Kwon JH; Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea., Namgoong JM; Division of Pediatric Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Song GW; Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Hwang S; Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Tak E; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Department of Biochemistry and Molecular Biology, AMIST, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Lee SG; Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2024 Jul; Vol. 28 (14), pp. e18533.
DOI: 10.1111/jcmm.18533
Abstrakt: 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.
(© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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