School of Chinese Medicine, the University of Hong Kong, Academic Building at No. 3 Sassoon Road, Pokfulam, Hong Kong S.A.R., China.
School of Chinese Medicine, the University of Hong Kong, Academic Building at No. 3 Sassoon Road, Pokfulam, Hong Kong S.A.R., China.
Phytomedicine. 2024 Oct;133:155913. doi: 10.1016/j.phymed.2024.155913. Epub 2024 Jul 25.
Human hepatocellular carcinoma (HCC) acquired resistance to anti-cancer agents due to the presence of immunosuppressive tumour microenvironment (TME) established by the interaction between tumour cells and immune populations. New treatment targeting the interaction is urgently needed and clinically beneficial to patients with HCC. This study aims to explore the anti-tumour effect of a Traditional Chinese Medicine formula Siwu Decoction (SWD) and its potential mechanism.
The chemical profile of SWD was determined by high-performance liquid chromatography coupled with mass spectrometry. In vitro and in vivo effects of SWD in regressing HCC were assessed. The role of myeloid-derived suppressor cells (MDSCs) in mediating SWD-induced HCC inhibition was determined by adoptive transfer assay. The regulation of SWD-induced interaction between HCC cells and MDSCs was also confirmed both in vitro and in vivo.
SWD dose-dependent inhibited the HCC growth and lung metastasis in an orthotopic growth tumour in mice, without significant toxicity and adverse side effect. SWD induced necroptosis in HCC cells, but did not directly inhibit in vitro culture of MDSCs, instead, SWD-treated HCC cell culture supernatant suppressed MDSCs by inducing its cell apoptosis. The necroptotic response of HCC cells can also suppress the MDSCs population in the TME without reducing circulating MDSCs infiltration into the tumours. Adoptive transfer of MDSCs recovered tumour growth and lung metastasis of HCC in SWD-treated mice. In HCC cells, SWD induced a necroptotic response, and blockade of necroptotic response in HCC cells recovered the MDSCs population in vitro and in vivo, and restored tumour growth and lung metastasis in SWD-treated mice. A combination of SWD improves the anti-HCC efficacy of sorafenib without inducing adverse side effects. Albiflorin, the effective compound of SWD, its anti-HCC manner has been verified to be consistent with that of SWD.
Our study observed for the first time that SWD can suppress HCC by regulating MDSCs through necroptosis of tumour cells in the TME. The main effective compound of SWD, albiflorin can be a potential adjuvant therapy in the clinical management of human HCC.
由于肿瘤细胞与免疫细胞群体相互作用而建立的免疫抑制肿瘤微环境（TME），人类肝细胞癌（HCC）对抗癌药物产生了获得性耐药。迫切需要针对这种相互作用的新治疗方法，这对 HCC 患者具有临床益处。本研究旨在探索四物汤（SWD）的抗肿瘤作用及其潜在机制。
采用高效液相色谱-质谱联用技术测定 SWD 的化学成分。评估 SWD 在消退 HCC 中的体外和体内作用。通过过继转移试验确定髓源性抑制细胞（MDSCs）在介导 SWD 诱导的 HCC 抑制中的作用。还在体外和体内证实了 SWD 诱导的 HCC 细胞与 MDSCs 之间相互作用的调节。
SWD 呈剂量依赖性抑制荷瘤小鼠原位生长肿瘤的生长和肺转移，且无明显毒性和不良反应。SWD 诱导 HCC 细胞发生坏死性凋亡，但不能直接抑制体外培养的 MDSCs，相反，SWD 处理的 HCC 细胞培养上清通过诱导其细胞凋亡抑制 MDSCs。HCC 细胞的坏死性凋亡反应也可以抑制 TME 中的 MDSCs 群体，而不会减少循环 MDSCs 浸润到肿瘤中。过继转移 MDSCs 恢复了 SWD 治疗小鼠的肿瘤生长和肺转移。在 HCC 细胞中，SWD 诱导了坏死性凋亡反应，阻断 HCC 细胞中的坏死性凋亡反应恢复了体外和体内的 MDSCs 群体，并恢复了 SWD 治疗小鼠的肿瘤生长和肺转移。SWD 联合治疗可提高索拉非尼的抗 HCC 疗效，而不会引起不良反应。SWD 的有效化合物白芍苷已被证实其抗 HCC 方式与 SWD 一致。
本研究首次观察到，SWD 可通过调节肿瘤细胞在 TME 中的 MDSCs 来抑制 HCC。SWD 的主要有效化合物白芍苷可能是人类 HCC 临床治疗的潜在辅助治疗药物。
