Apoptosis-Inducing and Proliferation-Inhibiting Effects of Doramectin on Mz-ChA-1 Human Cholangiocarcinoma Cells
Yunfang Zhang1, Wei Wu1, Yan Shi1
1State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China.
Abstract:
Cholangiocarcinoma is a malignant tumor that emerges in the intrahepatic or extrahepatic bile ducts. Doramectin (DOR), a third-generation derivative of avermectins (AVMs), is renowned for its low toxicity and high efficiency. However, no research has hitherto focused on the anti-cholangiocarcinoma effects of these drugs. In this study, we undertook a preliminary exploration of the mechanism through which DOR inhibits the viability of human cholangiocarcinoma cells (Mz-ChA-1) via transcriptome analysis and molecular validation at the cellular level. The results indicated that DOR could suppress the growth and proliferation of Mz-ChA-1 cells in a dose-dependent manner. Moreover, it significantly diminished their migration and invasion abilities. Cell cycle analysis disclosed arrest in the G1 phase, accompanied by an increase in p21 expression and a decrease in the levels of the cyclin E1 and CDK2 proteins. Additionally, DOR induced apoptosis via the ROS-triggered mitochondrial pathway. This was attested by an elevation in the BAX/BCL-2 ratio, the activation of caspase 3/7 and the cleavage of PARP1. These mechanistic insights underscore DOR's potential as a therapeutic agent against cholangiocarcinoma.
Insights
Doramectin (DOR) effectively suppresses cholangiocarcinoma cell growth, migration, and invasion. This avermectin derivative induces cell cycle arrest and apoptosis, highlighting its potential as a novel cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cholangiocarcinoma (CCA) is a bile duct cancer with limited treatment options.
- Avermectins (AVMs), like Doramectin (DOR), are known for low toxicity and high efficacy.
- The anti-cancer effects of DOR on CCA remain unexplored.
Purpose of the Study:
- To investigate the anti-cholangiocarcinoma effects of Doramectin (DOR).
- To elucidate the underlying molecular mechanisms of DOR's action on human cholangiocarcinoma cells (Mz-ChA-1).
Main Methods:
- Transcriptome analysis and molecular validation in Mz-ChA-1 cells.
- Cell viability, migration, and invasion assays.
- Cell cycle analysis, apoptosis assays, and Western blotting.
Main Results:
- DOR suppressed Mz-ChA-1 cell growth, proliferation, migration, and invasion in a dose-dependent manner.
- DOR induced G1 phase cell cycle arrest, increasing p21 and decreasing cyclin E1/CDK2.
- DOR triggered apoptosis via the ROS-mediated mitochondrial pathway, evidenced by altered BAX/BCL-2 ratio, activated caspase 3/7, and cleaved PARP1.
Conclusions:
- Doramectin demonstrates significant anti-cholangiocarcinoma activity at the cellular level.
- DOR's mechanism involves cell cycle arrest and apoptosis induction through the mitochondrial pathway.
- These findings suggest DOR holds therapeutic potential for treating cholangiocarcinoma.
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