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1.
Hepatol Commun ; 8(1)2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38180972

ABSTRACT

BACKGROUND: Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs. METHODS: The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the insulin receptor (INSR) was investigated by thermal shift assays. RESULTS: NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRß and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRß. CONCLUSIONS: NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B.


Subject(s)
Carcinoma, Hepatocellular , Hepatitis B, Chronic , Hepatitis B , Liver Neoplasms , Humans , Hepatitis B virus , Carcinoma, Hepatocellular/drug therapy , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/drug therapy , Proto-Oncogene Proteins c-akt , Liver Neoplasms/drug therapy , Hepatitis B/complications , Hepatitis B/drug therapy , Hepatocytes , Tenofovir/pharmacology , Tenofovir/therapeutic use , Intercellular Signaling Peptides and Proteins , Nucleotides
2.
Intern Med ; 46(5): 251-4, 2007.
Article in English | MEDLINE | ID: mdl-17329922

ABSTRACT

We report a patient with Sjögren's syndrome and chronic natural killer lymphocytosis, who developed severe neutropenia, autoimmune hemolytic anemia, and immune thrombocytopenia. High-dose prednisolone therapy improved the hemolytic anemia and thrombocytopenia, but not the CD16(+) CD56(-) NK lymphocytosis completely. Interestingly, indomethacin farnesil (a prodrug of indomethacin) was effective for myalgia and also decreased the number of CD16(+) CD56(-) NK cells. NK lymphocytosis is rarely associated with autoimmune disease, but the combination of indomethacin and steroid therapy may have a favorable effect for such patients.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Glucocorticoids/therapeutic use , Indomethacin/analogs & derivatives , Killer Cells, Natural/pathology , Lymphocytosis/etiology , Prednisolone/therapeutic use , Sjogren's Syndrome/complications , Sjogren's Syndrome/drug therapy , Adult , Chronic Disease , Female , Humans , Indomethacin/therapeutic use , Lymphocytosis/pathology , Sialadenitis/etiology , Sialadenitis/pathology , Treatment Outcome
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