Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, 110042, Liaoning, China.
Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, 110042, Liaoning, China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 2):117270. doi: 10.1016/j.jep.2023.117270. Epub 2023 Oct 11.
Huaier (Trametes robiniophila Murr), a traditional Chinese medicinal fungus, possesses potent anticancer efficacy and has been used as an adjuvant medication for liver, breast, gastric, intestinal, and non-small cell lung cancer (NSCLC). However, the potential regulatory functions and underlying molecular mechanisms of Huaier in cisplatin resistance of NSCLC remain unknown.
To evaluate the potential regulatory functions and underlying molecular mechanisms of Huaier in cisplatin resistance of NSCLC.
In vitro and in vivo experiments were employed to evaluate the regulatory functions of Huaier in cisplatin-resistant NSCLC cells. Transcriptome sequencing and validation analyses was undertaken to identify the downstream targets of Huaier. Network pharmacology, ultra-performance liquid chromatography-mass spectroscopy, and in vitro and in vivo experiments were performed to identify key small molecule drug candidates in Huaier and the regulatory mechanisms these employ to suppress cisplatin resistance in NSCLC.
Huaier suppressed cisplatin resistance and cancer cell stemness in cisplatin-resistant NSCLC cells, both in vitro and in vivo. Mechanistically, Huaier could suppress expression of interleuken-8 (IL-8) through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein-1 (AP-1), two key transcription factors responsible for the activation of IL-8 transcription. Kaempferol was identified as one of the key small molecule compounds in Huaier that could suppress cisplatin resistance by inhibiting the phosphorylation and nuclear translocation of proto-oncogene c-Jun (JUN) by binding and inhibiting the kinase activity of c-Jun N-terminal protein kinase (JNK).
Huaier suppressed cisplatin resistance of NSCLC cells by inhibiting the JNK/JUN/IL-8 signaling pathway.
药用真菌桑黄通过抑制 JNK/JUN/IL-8 信号通路抑制非小细胞肺癌顺铂耐药性
目的：评估药用真菌桑黄在非小细胞肺癌顺铂耐药中的调控作用及其潜在分子机制。
材料与方法：采用体外和体内实验评估桑黄对顺铂耐药非小细胞肺癌细胞的调控作用。通过转录组测序和验证分析，鉴定桑黄的下游靶点。采用网络药理学、超高效液相色谱-质谱联用技术、体外和体内实验，鉴定桑黄中的关键小分子候选药物及其抑制非小细胞肺癌顺铂耐药的调控机制。
结果：桑黄在体外和体内均能抑制顺铂耐药非小细胞肺癌细胞的顺铂耐药性和肿瘤细胞干性。机制上，桑黄通过抑制核因子κB（NF-κB）和激活蛋白-1（AP-1）这两个负责 IL-8 转录激活的关键转录因子，抑制白细胞介素-8（IL-8）的表达。山奈酚被鉴定为桑黄中的一种关键小分子化合物，通过与 c-Jun N 端蛋白激酶（JNK）结合并抑制其激酶活性，抑制原癌基因 c-Jun（JUN）的磷酸化和核易位，从而抑制 JNK/JUN/IL-8 信号通路，抑制顺铂耐药。
结论：桑黄通过抑制 JNK/JUN/IL-8 信号通路抑制非小细胞肺癌顺铂耐药性。
