Yang Ziwen, Syed Faizan Ali Shah, Huang Xinhui, Wei Lin, Zhong Yinze, Shi Xuepeng, Wu Xiaotian, Gan Chunli, Wang Zhibin, Yang Chunjuan
Department of Pharmaceutical Analysis and Analytical Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150000, China.
Key Laboratory of Basic and Application Research of Beiyao, Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin 150000, China.
Int J Mol Sci. 2025 Apr 9;26(8):3506. doi: 10.3390/ijms26083506.
Globally, lung cancer is the primary cause of deaths associated with cancer; however, current therapies are costly and toxic, highlighting the need for novel treatments. Peiminine (Verticinone), a key bioactive compound derived from Maxim., has demonstrated diverse biological activities. However, the precise pharmacological mechanisms underlying its anti-lung cancer effects remain unclear. The objective of this study was to quantify the content of peiminine in Maxim. from different geographical regions using UHPLC-MS/MS and to elucidate the anti-lung cancer mechanisms of peiminine through network pharmacology, bioinformatics, and in vitro experiments. The content of peiminine in Maxim. from various regions was determined using UHPLC-MS/MS. Potential target genes associated with peiminine and lung cancer were systematically screened from multiple databases. To identify core genes, we set up a PPI (protein-protein interaction) network, followed by in-depth analyses of their corresponding target proteins. Survival analysis, molecular docking, and dynamics simulations were used to explore potential anti-cancer mechanisms. In vitro experiments on human H1299 NSCLC cells assessed peiminine's anti-tumor activity and measured key gene transcription levels. UHPLC-MS/MS analysis revealed that Maxim. from Mudanjiang (Heilongjiang Province) exhibited the highest peiminine content. Network pharmacological analysis identified PIK3CG, SRC, JAK3, AKT2, and PRKCA as key potential targets of peiminine in lung cancer treatment. Molecular docking results demonstrated strong binding affinities between peiminine and PIK3CG, SRC, and JAK3; these results were further confirmed using molecular dynamics simulations. Survival analysis indicated that a high AKT2 and PRKCA expression correlated with bad prognosis in lung cancer patients. In vitro, peiminine inhibited H1299 cell viability and regulated genes involved in the PI3K-Akt pathway (PI3K, AKT, and PTEN) and apoptosis (Bcl-2, Bax), suggesting that it may induce its effects via PI3K-Akt pathway inhibition. Peiminine from Maxim. exhibits significant anti-lung cancer potential by targeting key genes such as PIK3CG, SRC, and JAK3, as well as by modulating the PI3K-Akt signaling pathway and apoptosis-related genes. These results lay a foundation for further investigations into peiminine as a potentially effective therapeutic option for treating lung cancer. Additionally, the identified targets (PIK3CG, SRC, JAK3, AKT2, and PRKCA) may function as possible biomarkers for predicting lung cancer prognosis and guiding personalized therapy.
在全球范围内，肺癌是与癌症相关的主要死亡原因；然而，目前的治疗方法成本高昂且有毒性，这凸显了对新型治疗方法的需求。浙贝母碱（贝母素乙）是从浙贝母中提取的一种关键生物活性化合物，已显示出多种生物活性。然而，其抗肺癌作用背后的确切药理机制仍不清楚。本研究的目的是使用超高效液相色谱-串联质谱法（UHPLC-MS/MS）定量分析不同地理区域浙贝母中浙贝母碱的含量，并通过网络药理学、生物信息学和体外实验阐明浙贝母碱的抗肺癌机制。使用UHPLC-MS/MS测定了不同地区浙贝母中浙贝母碱的含量。从多个数据库中系统筛选了与浙贝母碱和肺癌相关的潜在靶基因。为了确定核心基因，我们构建了一个蛋白质-蛋白质相互作用（PPI）网络，随后对其相应的靶蛋白进行深入分析。采用生存分析、分子对接和动力学模拟来探索潜在的抗癌机制。对人H1299非小细胞肺癌细胞进行体外实验，评估浙贝母碱的抗肿瘤活性并检测关键基因的转录水平。UHPLC-MS/MS分析显示，黑龙江牡丹江产的浙贝母中浙贝母碱含量最高。网络药理学分析确定PIK3CG、SRC、JAK3、AKT2和PRKCA是浙贝母碱在肺癌治疗中的关键潜在靶点。分子对接结果表明浙贝母碱与PIK3CG、SRC和JAK3之间具有很强的结合亲和力；分子动力学模拟进一步证实了这些结果。生存分析表明，AKT2和PRKCA高表达与肺癌患者的不良预后相关。在体外，浙贝母碱抑制H1299细胞活力，并调节参与PI3K-Akt通路（PI3K、AKT和PTEN）和凋亡（Bcl-2、Bax）的基因，表明它可能通过抑制PI3K-Akt通路发挥作用。浙贝母中的浙贝母碱通过靶向PIK3CG、SRC和JAK3等关键基因，以及调节PI3K-Akt信号通路和凋亡相关基因，展现出显著的抗肺癌潜力。这些结果为进一步研究浙贝母碱作为一种潜在有效的肺癌治疗选择奠定了基础。此外，所确定的靶点（PIK3CG、SRC、JAK3、AKT2和PRKCA）可能作为预测肺癌预后和指导个性化治疗的潜在生物标志物。
