Zhang Lu, Liu Songyu, Ding Kai, Zeng Bin, Li Bo, Zhou Jinyi, Li Jv, Wang Junliang, Su Xiaosan, Sun Ruifen
School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China.
Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
J Ethnopharmacol. 2025 Jan 31;340:119257. doi: 10.1016/j.jep.2024.119257. Epub 2024 Dec 16.
Positive deficiency and cancer toxicity are the main pathogenesis of colorectal cancer (CRC) lung metastasis. Yanghe decoction (YHD), a traditional Chinese medicine, has the effects of warming yang, tonifying blood, dispersing cold and clearing stagnation, adopting a treatment method that combines supporting the right and dispelling the wrong, which has remarkable efficacy in anti-tumor.Although, its precise mechanism of inhibiting the metastasis of colorectal cancer to the lung is still poorly understood.
This study aimed to elucidate the antitumor properties of YHD within the context of colorectal cancer lung metastasis.
Ultrahigh-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) was utilized to analyze the chemical composition of YHD. The anticancer activity of YHD was evaluated in a CRC lung metastasis mouse model by quantifying pulmonary metastatic nodules. The effects of YHD on CRC cell proliferation, apoptosis, cell cycle progression, and invasion were assessed using CCK-8 assays, flow cytometry, and Transwell assays. YHD-mediated immune modulation in tumor-bearing mice was evaluated by analyzing antitumor immunity, immunosuppressive cells, and cytokines in peripheral blood and tumor tissue. Gut microbiota analysis was conducted to determine the impact of YHD on the gut microbiota in mice.
Our analysis identified 1801 chemical markers in YHD. CFA exacerbated lung metastasis in CRC, whereas oral administration of YHD significantly mitigated this effect, as evidenced by the reduced number of metastatic lung nodules in CRC tumor-bearing mice. In vitro experiments demonstrated that YHD inhibits CRC cell proliferation, induces apoptosis, and suppresses invasion. In the lung tissues of mice with CRC metastasis treated with CFA, there was a significant reduction in NK cells and IL-21, along with an increase in M2 macrophages and IL-6. Following YHD treatment, there was a notable increase in NK cells and IL-21, accompanied by a decrease in M2 macrophages and IL-6 in lung tissues. YHD administration was also associated with an increase in beneficial bacterial species such as Bacillus and a decrease in deleterious bacterial species such as Oscillibacter.
Our findings demonstrate that YHD inhibits lung metastasis in CRC by suppressing CRC cell proliferation and invasion, in addition to modulating the tumor microenvironment to favor antitumor immunity. These results provide a scientific basis for the clinical application of YHD in the treatment of CRC patients.
正虚毒结是结直肠癌（CRC）肺转移的主要发病机制。阳和汤（YHD）作为一种中药，具有温阳补血、散寒通滞之功效，采用扶正祛邪相结合的治疗方法，在抗肿瘤方面疗效显著。然而，其抑制结直肠癌肺转移的确切机制仍不清楚。
本研究旨在阐明阳和汤在结直肠癌肺转移背景下的抗肿瘤特性。
采用超高效液相色谱-质谱联用（UHPLC-MS）分析阳和汤的化学成分。通过定量肺转移结节，在结直肠癌肺转移小鼠模型中评估阳和汤的抗癌活性。使用CCK-8法、流式细胞术和Transwell法评估阳和汤对结直肠癌细胞增殖、凋亡、细胞周期进程和侵袭的影响。通过分析外周血和肿瘤组织中的抗肿瘤免疫、免疫抑制细胞和细胞因子，评估阳和汤在荷瘤小鼠中介导的免疫调节作用。进行肠道微生物群分析，以确定阳和汤对小鼠肠道微生物群的影响。
我们的分析在阳和汤中鉴定出1801种化学标志物。环磷酰胺（CFA）加剧了结直肠癌的肺转移，而口服阳和汤显著减轻了这种作用，结直肠癌荷瘤小鼠肺转移结节数量减少证明了这一点。体外实验表明，阳和汤抑制结直肠癌细胞增殖，诱导凋亡，并抑制侵袭。在接受CFA治疗的结直肠癌转移小鼠的肺组织中，自然杀伤细胞（NK细胞）和白细胞介素-21（IL-21）显著减少，同时M2巨噬细胞和白细胞介素-6（IL-6）增加。阳和汤治疗后，肺组织中NK细胞和IL-21显著增加，同时M2巨噬细胞和IL-6减少。阳和汤给药还与有益细菌种类如芽孢杆菌的增加和有害细菌种类如颤杆菌的减少有关。
我们的研究结果表明，阳和汤通过抑制结直肠癌细胞增殖和侵袭，以及调节肿瘤微环境以促进抗肿瘤免疫，从而抑制结直肠癌的肺转移。这些结果为阳和汤在结直肠癌患者治疗中的临床应用提供了科学依据。
