Enhanced inhibitory effects of mianserin in combination with sorafenib on liver cancer growth through targeting the CCR9-AKT pathway.

IF 2.9 3区 医学 Q2 ONCOLOGY
American journal of cancer research Pub Date : 2025-06-25 eCollection Date: 2025-01-01 DOI:10.62347/CYDE4091
Ya-Hui Huang, Chia-Jung Liao, Meng-Han Wu, Ming-Wei Lai, Yung-Hsin Yeh, Chau-Ting Yeh, Yang-Hsiang Lin, Kwang-Huei Lin
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引用次数: 0

Abstract

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 in vivo 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 in vivo 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 in vitro and in vivo experiments highlight mianserin's potential as an adjuvant therapy to sorafenib, offering a promising strategy to overcome current challenges in liver cancer treatment.

米安色林联合索拉非尼通过靶向CCR9-AKT通路增强对肝癌生长的抑制作用。
先前,我们的研究小组发现,非典型抗抑郁药米安色林对肝癌细胞的细胞毒性比正常肝细胞强,支持其作为肝癌治疗剂的潜在应用。然而,米安色林的体内抗肿瘤作用及其机制尚不明确。在本研究中,我们探讨了米安色林对肝癌细胞的抑制作用和机制,并评估了其与索拉非尼联合对肝癌细胞的抑制作用。通过MTT和流式细胞术检测评估对细胞活力的影响,并使用异种移植物模型评估抗肿瘤活性。通过免疫印迹法检测细胞内特定蛋白的表达和分布变化。我们的研究结果表明,米安色林通过抑制细胞增殖和诱导细胞凋亡来抑制细胞活力,从而发挥细胞毒性作用。通过异种移植瘤模型瘤内注射验证了米安色林的治疗效果。在机制上,我们的数据表明,米安色林诱导的细胞质HSP60易位到细胞表面并参与CCR9的下调,导致AKT-(β-catenin/NFκB)信号通路失活。米安色林和索拉非尼联合治疗对亲代和索拉非尼耐药肝癌细胞的细胞活力、细胞凋亡和体内肿瘤生长均有显著的协同作用。本研究首次证实米安色林通过下调CCR9,进而使AKT-(β-catenin/NFκB)通路失活,从而有效限制肝癌的生长。体外和体内实验都强调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希望的策略。
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来源期刊
自引率
3.80%
发文量
263
期刊介绍: The American Journal of Cancer Research (AJCR) (ISSN 2156-6976), is an independent open access, online only journal to facilitate rapid dissemination of novel discoveries in basic science and treatment of cancer. It was founded by a group of scientists for cancer research and clinical academic oncologists from around the world, who are devoted to the promotion and advancement of our understanding of the cancer and its treatment. The scope of AJCR is intended to encompass that of multi-disciplinary researchers from any scientific discipline where the primary focus of the research is to increase and integrate knowledge about etiology and molecular mechanisms of carcinogenesis with the ultimate aim of advancing the cure and prevention of this increasingly devastating disease. To achieve these aims AJCR will publish review articles, original articles and new techniques in cancer research and therapy. It will also publish hypothesis, case reports and letter to the editor. Unlike most other open access online journals, AJCR will keep most of the traditional features of paper print that we are all familiar with, such as continuous volume, issue numbers, as well as continuous page numbers to retain our comfortable familiarity towards an academic journal.
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