Zhang Yunfang, Wu Wei, Shi Yan, Huang Yuehong, Dai Ting, Ke Lina, Chen Lizhu, Chen Mingliang, Wang Qin
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China.
Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China.
Int J Mol Sci. 2024 Dec 15;25(24):13440. doi: 10.3390/ijms252413440.
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.
胆管癌是一种发生于肝内或肝外胆管的恶性肿瘤。多拉菌素（DOR）是阿维菌素（AVMs）的第三代衍生物，以其低毒性和高效性而闻名。然而，迄今为止尚无研究关注这些药物的抗胆管癌作用。在本研究中，我们通过转录组分析和细胞水平的分子验证，对DOR抑制人胆管癌细胞（Mz-ChA-1）活力的机制进行了初步探索。结果表明，DOR能以剂量依赖的方式抑制Mz-ChA-1细胞的生长和增殖。此外，它还显著降低了细胞的迁移和侵袭能力。细胞周期分析显示细胞停滞于G1期，伴随着p21表达增加以及细胞周期蛋白E1和CDK2蛋白水平降低。此外，DOR通过活性氧触发的线粒体途径诱导细胞凋亡。这通过BAX/BCL-2比值升高、caspase 3/7激活和PARP1裂解得到证实。这些机制性见解突显了DOR作为胆管癌治疗药物的潜力。
