Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Hepatol Commun. 2024 Jan 5;8(1). doi: 10.1097/HC9.0000000000000351. eCollection 2024 Jan 1.
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.
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.
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)-INSRβ 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 INSRβ.
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.
最近的临床研究表明，接受替诺福韦酯治疗的慢性乙型肝炎患者发生 HCC 的风险可能低于接受恩替卡韦治疗的患者，尽管这两种药物在生化和病毒学缓解方面没有差异。
在体外研究了核苷类似物（拉米夫定和恩替卡韦）或核苷酸类似物（阿德福韦酯、替诺福韦酯富马酸和替诺福韦艾拉酚胺）对肝癌细胞系和 PXB 细胞的细胞生长和生长信号分子表达的影响。在小鼠异种移植模型中评估了 NsAs 或 NtAs 的肿瘤抑制作用，并研究了蛋白质磷酸化谱。通过热移位测定研究了 NsAs 或 NtAs 与胰岛素受体（INSR）的结合。
NtAs 而非 NsAs 在体外肝癌细胞系和体内小鼠模型中均显示出直接的生长抑制作用。磷酸蛋白芯片显示，胰岛素受体信号受损，磷酸化（p）-INSRβ 和下游分子磷酸化（p）-IRS1、p-AKT、p-Gab1 和 p-SHP2 的水平显著降低。此外，NtAs 还降低了 p-表皮生长因子受体和 p-AKT 的水平。在 PXB 细胞和慢性乙型肝炎患者肝组织的非肿瘤病变中也发现了类似的发现。前药 NtAs，但不是它们的代谢物（阿德福韦、阿德福韦单磷酸盐、阿德福韦二磷酸盐、替诺福韦、替诺福韦单磷酸盐和替诺福韦二磷酸盐），具有这种作用。热移位测定显示 NtAs 与 INSRβ 的结合。
NtAs（阿德福韦酯、替诺福韦酯富马酸和替诺福韦艾拉酚胺），是腺嘌呤衍生物无环核苷酸类似物，可能与生长因子受体的 ATP 结合位点结合并抑制其自身磷酸化，从而降低慢性乙型肝炎患者发生 HCC 的风险。
