Huang Ya-Hui, Liao Chia-Jung, Wu Meng-Han, Lai Ming-Wei, Yeh Yung-Hsin, Yeh Chau-Ting, Lin Yang-Hsiang, Lin Kwang-Huei
Liver Research Center, Chang Gung Memorial Hospital, Linkou Main Branch Taoyuan, Taiwan.
Molecular Medicine Research Center, Chang-Gung University Taoyuan, Taiwan.
Am J Cancer Res. 2025 Jun 25;15(6):2890-2904. doi: 10.62347/CYDE4091. eCollection 2025.
Previously, our group showed that mianserin, an atypical antidepressant, exerts stronger cytotoxicity against liver cancer cells than normal hepatocytes, supporting its potential application as a therapeutic agent for liver cancer. However, the anti-tumor effects of mianserin and its mechanisms are yet to be established. In this study, we explored the inhibitory effects and mechanisms of mianserin and evaluated its efficacy in combination with sorafenib against liver cancer cells. Effects on cell viability were assessed via MTT and flow cytometry assays and antitumor activity evaluated using a xenograft model. Changes in the expression and distribution of specific proteins within cells were examined via immunoblot assay. Our results indicate that mianserin exerts cytotoxic effects by inhibiting cell viability through suppression of proliferation and induction of apoptosis. Therapeutic effects of mianserin were validated via intratumoral injection in the xenograft model. Mechanistically, our data indicate that mianserin-induced cytosolic HSP60 translocates to cell surface and participates in the downregulation of CCR9, leading to inactivation of the AKT-(β-catenin/NFκB) signaling pathway. Combination treatment with mianserin and sorafenib induced significant synergistic effects on cell viability, apoptosis, and tumor growth in both parental and sorafenib-resistant liver cancer cells. This study is the first to demonstrated that mianserin effectively limits the growth of liver cancer by downregulating CCR9, in turn, inactivating the AKT-(β-catenin/NFκB) pathway. Both and experiments highlight mianserin's potential as an adjuvant therapy to sorafenib, offering a promising strategy to overcome current challenges in liver cancer treatment.
此前，我们团队发现，非典型抗抑郁药米安色林对肝癌细胞的细胞毒性比对正常肝细胞更强，这支持了其作为肝癌治疗药物的潜在应用价值。然而，米安色林的抗肿瘤作用及其机制尚未明确。在本研究中，我们探究了米安色林的抑制作用及其机制，并评估了其与索拉非尼联合使用对肝癌细胞的疗效。通过MTT和流式细胞术检测评估对细胞活力的影响，并使用异种移植模型评估抗肿瘤活性。通过免疫印迹分析检测细胞内特定蛋白质的表达和分布变化。我们的结果表明，米安色林通过抑制增殖和诱导凋亡来抑制细胞活力，从而发挥细胞毒性作用。通过在异种移植模型中瘤内注射验证了米安色林的治疗效果。从机制上讲，我们的数据表明，米安色林诱导的胞质HSP60转运至细胞表面并参与CCR9的下调，导致AKT-（β-连环蛋白/NFκB）信号通路失活。米安色林与索拉非尼联合治疗对亲本和索拉非尼耐药的肝癌细胞的细胞活力、凋亡和肿瘤生长均产生显著的协同作用。本研究首次证明，米安色林通过下调CCR9有效限制肝癌生长，进而使AKT-（β-连环蛋白/NFκB）通路失活。体内和体外实验均凸显了米安色林作为索拉非尼辅助治疗的潜力，为克服当前肝癌治疗中的挑战提供了一种有前景的策略。
