Abstract Context Ursolic acid (UA), a natural product, shows a broad spectrum of anticancer effects. However, the poor bioavailability and efficacy of UA limit its clinical application. Objective We developed novel analogues of UA with enhanced antitumor activities by the extensive chemical modification of UA. Materials and methods We developed multiple compounds by structural modification of UA, and found that UA232 had stronger activity than UA. The effects of UA232 (0–50 μM) on inhibiting the proliferation of A549 and H460 cells were determined by CCK-8 for 24, 48, or 72 h. The proapoptotic effect of UA232 was analyzed by microscopy and flow cytometry, and the potential signal pathway affected by UA232 was further validated by Western blotting and flow cytometry. Results Compared with UA, UA232 showed a stronger ability to inhibit the proliferation of lung cancer cells (IC50 = 5.4–6.1 μM for A549 and 3.9–5.7 μM for H460 cells). UA232 could induce not only cell cycle arrest in the G0/G1 phase but also apoptosis in both A549 and H460 cells. The treatment of UA232 could lead to an increase of CHOP expression rather than an increase in Bax or caspase-8, indicating that the apoptosis induced by UA232 was correlated with the endoplasmic reticulum stress (ER stress) pathway. Treatment with the ER stress-specific inhibitor, 4-PBA, decreased the ability of UA232 to induce apoptosis in A549 and H460 cells. Conclusion UA232 induced apoptosis through the ER stress pathway, and showed stronger growth-inhibitory effects in A549 and H460 cells compared to UA, which may be a potential anticancer drug to suppress the proliferation of lung cancer.

中文翻译：

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熊果酸衍生物UA232诱发内质网应激诱导的肺癌细胞凋亡


摘要背景熊果酸（UA）是一种天然产物，具有广泛的抗癌作用。然而UA的生物利用度和疗效较差限制了其临床应用。目的 我们通过对 UA 进行广泛的化学修饰，开发出具有增强抗肿瘤活性的新型 UA 类似物。材料与方法我们通过UA的结构修饰开发了多种化合物，发现UA232比UA具有更强的活性。通过 CCK-8 测定 UA232 (0–50 μM) 对 A549 和 H460 细胞增殖的抑制作用，作用时间为 24、48 或 72 小时。通过显微镜和流式细胞术分析UA232的促凋亡作用，并通过Western blotting和流式细胞术进一步验证UA232影响的潜在信号通路。结果 与UA相比，UA232表现出更强的抑制肺癌细胞增殖的能力（A549细胞的IC50 = 5.4-6.1 μM，H460细胞的IC50 = 3.9-5.7 μM）。 UA232不仅可以诱导A549和H460细胞的细胞周期停滞在G0/G1期，而且可以诱导细胞凋亡。 UA232处理可导致CHOP表达增加，而不是Bax或caspase-8增加，表明UA232诱导的细胞凋亡与内质网应激（ER应激）途径相关。用 ER 应激特异性抑制剂 4-PBA 处理，降低了 UA232 诱导 A549 和 H460 细胞凋亡的能力。结论 UA232通过ER应激途径诱导细胞凋亡，且对A549和H460细胞具有较UA更强的生长抑制作用，可能是抑制肺癌增殖的潜在抗癌药物。