{"title":"Enhanced inhibitory effects of mianserin in combination with sorafenib on liver cancer growth through targeting the CCR9-AKT pathway.","authors":"Ya-Hui Huang, Chia-Jung Liao, Meng-Han Wu, Ming-Wei Lai, Yung-Hsin Yeh, Chau-Ting Yeh, Yang-Hsiang Lin, Kwang-Huei Lin","doi":"10.62347/CYDE4091","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>in vivo</i> 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 <i>in vivo</i> 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 <i>in vitro</i> and <i>in vivo</i> experiments highlight mianserin's potential as an adjuvant therapy to sorafenib, offering a promising strategy to overcome current challenges in liver cancer treatment.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 6","pages":"2890-2904"},"PeriodicalIF":2.9000,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256417/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.62347/CYDE4091","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
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.
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.