Preliminary exploration of the pharmacological effects and mechanisms of icaritin in regulating macrophage polarization for the treatment of intrahepatic cholangiocarcinoma
10.16438/j.0513-4870.2024-0265
- VernacularTitle:淫羊藿素调控巨噬细胞极化治疗肝内胆管癌的药效作用及机制初探
- Author:
Jing-wen WANG
1
,
2
;
Zhen LI
3
;
Xiu-qin HUANG
3
;
Zi-jing XU
3
;
Jia-hao GENG
3
;
Yan-yu XU
3
;
Tian-yi LIANG
3
;
Xiao-yan ZHAN
4
;
Li-ping KANG
5
;
Jia-bo WANG
1
,
2
,
6
;
Xin-hua SONG
3
Author Information
1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510000, China
2. School of Traditional Chinese Medicine, Capital Medical University, Beijing 100071, China
3. School of Traditional Chinese Medicine, Capital Medical University, Beijing 100071, China
4. Fifth Medical Center, PLA General Hospital, Beijing 100071, China
5. State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Beijing 100070, China
6. State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-Di Herbs, Beijing 100070, China
- Publication Type:Research Article
- Keywords:
intrahepatic cholangiocarcinoma;
icaritin;
immune microenvironment;
macrophage polarization;
Toll-like receptor 9
- From:
Acta Pharmaceutica Sinica
2024;59(8):2227-2236
- CountryChina
- Language:Chinese
-
Abstract:
The incidence of intrahepatic cholangiocarcinoma (ICC) continues to rise, and there are no effective drugs to treat it. The immune microenvironment plays an important role in the development of ICC and is currently a research hotspot. Icaritin (ICA) is an innovative traditional Chinese medicine for the treatment of advanced hepatocellular carcinoma. It is considered to have potential immunoregulatory and anti-tumor effects, which is potentially consistent with the understanding of "Fuzheng" in the treatment of tumor in traditional Chinese medicine. However, whether ICA can be used to treat ICC has not been reported. Therefore, in this study, sgp19/kRas, an in situ ICC mouse model with intact immune system, was selected to evaluate the efficacy of ICA in the treatment of ICC in vivo for the first time, and the effects of ICA on the tumor immune microenvironment of ICC mice were analyzed by flow cytometry. This experiment was approved by the Experimental Animal Ethics Committee of Capital Medical University (approval number: AEEI-2023-138). In this study, sgp19/kRas ICC mouse model was treated with oral gavage of 100 mg·kg-1 ICA. We found that ICA significantly inhibited tumor growth and tumor cell proliferation in the sgp19/kRas ICC mouse model after 3 weeks of treatment. Flow cytometry analysis indicated that ICA treatment markedly reduced the proportion of M2 macrophages and increased the number of CD3+CD4+ T cells. In vitro experiments demonstrated that ICA promoted macrophage polarization towards the M1 phenotype while inhibiting polarization towards the M2 phenotype. Furthermore, transcriptomic analysis suggested that ICA enhanced Toll-like receptor 9 (TLR9) expression, influencing macrophage nitric oxide metabolism synthesis pathways and receptor-related activities, thereby regulating macrophage polarization. In summary, this study demonstrates that ICA treatment significantly delays tumor progression in sgp19/kRas ICC mouse models. Mechanistically, ICA may achieve its anti-ICC effects by upregulating TLR9 receptor expression levels, promoting macrophage polarization towards the M1 phenotype, and altering the tumor immune microenvironment.
