Background/Objectives: Lung cancer is one of the deadliest cancers, and drug resistance complicates its treatment. Mahanine (MH), an alkaloid fromMurraya koenigiihas been known for its anti-cancer properties. However, its effectiveness and mechanisms in treating non-small cell lung cancer (NSCLC) remain largely unexplored. The present study aimed to investigate MH’s effect on drug-sensitive and drug-resistant NSCLC and its potential mechanism of action.Methods: We isolated MH fromM. koenigiileaves and the purity (99%) was confirmed by HPLC, LC-MS and NMR. The antiproliferative activity of MH was determined using MTT and colony formation assays against drug-sensitive (A549 and H1299) and Taxol-resistant lung cancer cells (A549-TR). Western blot analysis was performed to determine MH’s effects on various molecular targets. Anti-tumor activity of MH was determined against lung tumors developed in female NOD Scid mice injected with A549-Fluc bioluminescent cells (1.5 × 106) intrathoracically.Results: MH dose-dependently reduced the proliferation of all lung cancer cells (A549, H1299 and A549-TR), with IC50 values of 7.5, 5, and 10 µM, respectively. Mechanistically, MH arrested cell growth in the G0/G1 and G2/M phases of the cell cycle by inhibiting cyclin-dependent kinase 4/6 (CDK4/6) and cell division control 2 (CDC2) and induced apoptosis through the downregulation of B-cell leukemia/lymphoma 2 (BCL2) and B-cell lymphoma-extra large (BCL-XL). The apoptotic induction capacity of MH can also be attributed to its ability to inhibit pro-oncogenic markers, including mesenchymal–epithelial transition factor receptor (MET), phosphorylated protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), survivin, rat sarcoma viral oncogene (RAS), myelocytomatosis oncogene (cMYC), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) levels. In vivo, MH (25 mg/kg b. wt.) significantly (p< 0.001) inhibited the growth of A549 lung cancer orthotopic xenografts in NOD Scid mice by 70%.Conclusions: Our study provides new mechanistic insights into MH’s therapeutic potential against NSCLC.
背景/目的：肺癌是最致命的癌症之一，耐药性使其治疗复杂化。九里香碱（MH）是从九里香中提取的一种生物碱，以其抗癌特性而闻名。然而，其在治疗非小细胞肺癌（NSCLC）中的有效性和机制在很大程度上仍未得到探索。本研究旨在探讨MH对药物敏感型和耐药型NSCLC的作用及其潜在作用机制。 方法：我们从九里香叶中分离出MH，并通过高效液相色谱法、液相色谱-质谱联用和核磁共振确认其纯度（99%）。使用MTT法和集落形成实验测定MH对药物敏感型（A549和H1299）和紫杉醇耐药型肺癌细胞（A549-TR）的抗增殖活性。通过蛋白质印迹分析确定MH对各种分子靶点的影响。通过向雌性NOD Scid小鼠胸腔内注射A549-Fluc生物发光细胞（1.5 × 10^6）建立肺癌模型，评估MH的抗肿瘤活性。 结果：MH剂量依赖性地抑制所有肺癌细胞（A549、H1299和A549-TR）的增殖，IC50值分别为7.5、5和10 µM。机制上，MH通过抑制细胞周期蛋白依赖性激酶4/6（CDK4/6）和细胞分裂周期蛋白2（CDC2），将细胞周期阻滞在G0/G1和G2/M期，并通过下调B细胞白血病/淋巴瘤2（BCL2）和B细胞淋巴瘤-超大（BCL-XL）诱导细胞凋亡。MH的凋亡诱导能力还可归因于其抑制促癌标志物的能力，包括间质-上皮转化因子受体（MET）、磷酸化蛋白激酶B（p-AKT）、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）、生存素、大鼠肉瘤病毒癌基因（RAS）、髓细胞瘤癌基因（cMYC）和核因子κB（NF-κB）水平。在体内实验中，MH（25 mg/kg体重）显著（p<0.001）抑制NOD Scid小鼠中A549肺癌原位移植瘤的生长，抑制率达70%。 结论：我们的研究为MH治疗NSCLC的潜力提供了新的机制见解。
肿瘤(癌症)患者之家