Related Experiment Video
Updated: Aug 5, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Imipramine Reverses Sorafenib Resistance in Hepatocellular Carcinoma by Targeting the BLOC1S5/FOXO1 Signaling Axis
Yang-Hsiang Lin1, Yu-Chin Liu2, Chia-Jung Liao3
1Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Abstract:
Liver cancer, particularly hepatocellular carcinoma (HCC), is among the leading causes of cancer-related mortality worldwide, with drug resistance posing a significant therapeutic challenge. Therefore, overcoming this barrier is a critical step toward improving survival outcomes in patients with drug-resistant disease. Here, we demonstrate that the antidepressant imipramine effectively inhibits tumor growth in vitro and in vivo. Notably, imipramine enhances the anticancer efficacy of sorafenib, resulting in an additive suppression of tumor growth and cell migration. Moreover, imipramine treatment restores sensitivity in sorafenib-resistant hepatoma cells. RNA-sequencing analysis identified increased expression of BLOC1S5 in sorafenib-resistant cells compared to their parental counterparts. Functional assays indicated that overexpression of BLOC1S5 promotes tumor sphere formation, cell migration, sorafenib resistance, and metastasis through suppression of FOXO1. Imipramine treatment significantly reduced BLOC1S5 expression while inducing FOXO1 expression. Crucially, the inhibitory effect of imipramine on cell migration was reversed by BLOC1S5 overexpression, indicating that imipramine acts, at least in part, by suppressing this protein. Clinically, elevated BLOC1S5 expression correlated with poor prognosis, whereas higher FOXO1 levels were associated with favorable outcomes in HCC patients. Collectively, these results highlight the repurposing of imipramine as a promising therapeutic strategy to sensitize HCC cells to sorafenib via modulation of the BLOC1S5/FOXO1 signaling axis.
Insights
The antidepressant imipramine inhibits liver cancer growth and restores sensitivity to sorafenib. It targets BLOC1S5/FOXO1 signaling, offering a new therapeutic strategy for hepatocellular carcinoma (HCC).
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a major cause of cancer mortality, with drug resistance limiting treatment efficacy.
- Developing strategies to overcome drug resistance is crucial for improving patient survival in HCC.
Purpose of the Study:
- To investigate the potential of the antidepressant imipramine as a therapeutic agent for drug-resistant HCC.
- To elucidate the molecular mechanisms underlying imipramine's effects on HCC growth and sorafenib resistance.
Main Methods:
- In vitro and in vivo experiments assessing imipramine's effects on tumor growth and cell migration.
- RNA-sequencing to identify molecular targets of imipramine and sorafenib resistance.
- Functional assays to validate the role of BLOC1S5 and FOXO1 in HCC progression and drug response.
Main Results:
- Imipramine demonstrated significant inhibition of HCC tumor growth and cell migration, both alone and in combination with sorafenib.
- Imipramine restored sensitivity to sorafenib in resistant HCC cells by reducing BLOC1S5 expression and increasing FOXO1 expression.
- Overexpression of BLOC1S5 promoted HCC progression and drug resistance, while imipramine's effects were reversed by BLOC1S5 overexpression.
- Elevated BLOC1S5 correlated with poor prognosis, whereas higher FOXO1 levels were associated with favorable outcomes in HCC patients.
Conclusions:
- Imipramine shows promise as a repurposed drug for treating drug-resistant HCC.
- Modulating the BLOC1S5/FOXO1 signaling axis is a key mechanism by which imipramine enhances sorafenib efficacy.
- Imipramine represents a potential therapeutic strategy to overcome sorafenib resistance in hepatocellular carcinoma.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...