背景:肺癌,一种慢性异质性疾病,是全球范围内癌症相关死亡的主要原因。目前,尽管有各种各样的治疗方法,它们的有效性是有限的,往往导致相当大的毒性和不良反应。此外,癌细胞中化学抗性的发展提出了挑战。三叶内酯-6-O-异丁酸酯(TBB),从三叶草中提取的天然倍半萜内酯,具有抗肿瘤作用。其在NSCLC肺癌中的药理特性,然而,没有被探索过。
目的:本研究评估了TBB对体外A549和NCI-H460肿瘤细胞系的影响,检查其抗增殖特性和细胞死亡的初始机制。
方法:TBB,从S.trilobata叶以98%的纯度获得,使用色谱技术表征。随后,其对体外抑制肿瘤细胞增殖的影响,TBB对LLC-MK2,THP-1,AMJ2-C11细胞的细胞毒性,以及它对绵羊红细胞的影响,以及细胞死亡的潜在机制,被评估。
结果:在计算机预测中,TBB显示了有希望的药物相似潜力,表明高口服生物利用度和肠道吸收。用TBB处理A549和NCI-H460人肿瘤细胞表现出直接的影响,诱导显著的形态和结构改变。TBB还降低了迁移能力,而在较低浓度下对LLC-MK2、THP-1和AMJ2-C11细胞系不产生毒性。这种抗增殖作用与升高的氧化应激有关,以ROS水平增加为特征,超氧阴离子自由基和NO,伴随着抗氧化剂标志物的减少:SOD和GSH。TBB应激导致细胞代谢改变,促进脂滴和自噬液泡的积累。压力也导致线粒体完整性受损,细胞功能的关键方面。此外,TBB通过激活caspase3/7应激源促进凋亡样细胞死亡。
结论:这些发现强调了TBB作为未来研究的有希望的候选药物的潜力,并表明其作为新型抗癌药物原型开发的额外组成部分的可行性。
BACKGROUND: Lung cancer, a chronic and heterogeneous disease, is the leading cause of cancer-related death on a global scale. Presently, despite a variety of available treatments, their effectiveness is limited, often resulting in considerable toxicity and adverse effects. Additionally, the development of chemoresistance in cancer cells poses a challenge. Trilobolide-6-O-isobutyrate (TBB), a natural sesquiterpene lactone extracted from Sphagneticola trilobata, has exhibited antitumor effects. Its pharmacological properties in NSCLC lung cancer, however, have not been explored.
OBJECTIVE: This study evaluated the impact of TBB on the A549 and NCI-H460 tumor cell lines in vitro, examining its antiproliferative properties and initial mechanisms of cell death.
METHODS: TBB, obtained at 98 % purity from S. trilobata leaves, was characterized using chromatographic techniques. Subsequently, its impact on inhibiting tumor cell proliferation in vitro, TBB-induced cytotoxicity in LLC-MK2, THP-1, AMJ2-C11 cells, as well as its effects on sheep erythrocytes, and the underlying mechanisms of cell death, were assessed.
RESULTS: In silico predictions have shown promising drug-likeness potential for TBB, indicating high oral bioavailability and intestinal absorption. Treatment of A549 and NCI-H460 human tumor cells with TBB demonstrated a direct impact, inducing significant morphological and structural alterations. TBB also reduced migratory capacity without causing toxicity at lower concentrations to LLC-MK2, THP-1 and AMJ2-C11 cell lines. This antiproliferative effect correlated with elevated oxidative stress, characterized by increased levels of ROS, superoxide anion radicals and NO, accompanied by a decrease in antioxidant markers: SOD and GSH. TBB-stress-induced led to changes in cell metabolism, fostering the accumulation of lipid droplets and autophagic vacuoles. Stress also resulted in compromised mitochondrial integrity, a crucial aspect of cellular function. Additionally, TBB prompted apoptosis-like cell death through activation of caspase 3/7 stressors.
CONCLUSIONS: These findings underscore the potential of TBB as a promising candidate for future studies and suggest its viability as an additional component in the development of novel anticancer drugs prototypes.