Motoyama Makito, Shigefuku Ryota, Tanaka Noriyoshi, Nishizawa Mitsuaki, Oshio Keigo, Suhara Yoshitomo, Yajima Ichiro
Unit of Molecular and Cellular Toxicology, and Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Saitama, Japan.
Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Saitama, Japan.
Anticancer Res. 2025 Feb;45(2):433-443. doi: 10.21873/anticanres.17432.
BACKGROUND/AIM: Lung cancer is among the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Overactivation of the EGFR/AKT signaling pathway contributes significantly to NSCLC progression and metastasis. Cisplatin, a widely used chemotherapeutic agent, faces limitations due to severe side effects and the emergence of resistant cancer cells. Acyclic retinoid (ACR), a synthetic derivative of vitamin A, has shown antitumor effects in hepatocellular carcinoma, but its efficacy against NSCLC and cisplatin-resistant cells remains unclear. This study aimed to investigate whether ACR could inhibit EGFR/AKT signaling and enhance therapeutic efficacy against NSCLC and cisplatin-resistant cells.
Human NSCLC A549 cells, cisplatin-resistant A549 (A549CR) cells, and normal lung epithelial BEAS-2B cells were treated with ACR, alone or in combination with cisplatin. Cell viability, apoptosis, and changes in expression/phosphorylation of EGFR, AKT, and cell cycle regulators were assessed using cell viability assay, immunostaining, and immunoblotting.
ACR selectively reduced viability of A549 cells with less toxicity to BEAS-2B cells and induced apoptosis via cleaved Caspase-3 activation. ACR inhibited EGFR/AKT signaling and up-regulated p27 in A549 cells. The combination of ACR and cisplatin synergistically reduced cell viability and suppressed AKT phosphorylation. Notably, ACR also inhibited EGFR/AKT signaling in A549CR cells, restoring sensitivity to cisplatin and reversing EMT-like characteristics.
ACR effectively inhibits EGFR/AKT signaling and enhances cisplatin sensitivity in NSCLC and cisplatin-resistant cells, suggesting its potential as a promising therapeutic strategy for lung cancer.
背景/目的：肺癌是全球最常见且致命的恶性肿瘤之一，其中非小细胞肺癌（NSCLC）占大多数病例。表皮生长因子受体/蛋白激酶B（EGFR/AKT）信号通路的过度激活对NSCLC的进展和转移有显著影响。顺铂是一种广泛使用的化疗药物，但由于严重的副作用和耐药癌细胞的出现而存在局限性。无环维甲酸（ACR）是维生素A的合成衍生物，已在肝细胞癌中显示出抗肿瘤作用，但其对NSCLC和顺铂耐药细胞的疗效仍不清楚。本研究旨在探讨ACR是否能抑制EGFR/AKT信号传导，并增强对NSCLC和顺铂耐药细胞的治疗效果。
人NSCLC A549细胞、顺铂耐药A549（A549CR）细胞和正常肺上皮BEAS-2B细胞分别单独或与顺铂联合使用ACR进行处理。使用细胞活力测定、免疫染色和免疫印迹法评估细胞活力、凋亡以及EGFR、AKT和细胞周期调节因子的表达/磷酸化变化。
ACR选择性降低A549细胞的活力，对BEAS-2B细胞的毒性较小，并通过激活裂解的半胱天冬酶-3诱导凋亡。ACR抑制A549细胞中的EGFR/AKT信号传导并上调p27。AC和顺铂联合使用可协同降低细胞活力并抑制AKT磷酸化。值得注意的是，ACR还抑制A549CR细胞中的EGFR/AKT信号传导，恢复对顺铂的敏感性并逆转类似上皮-间质转化的特征。
ACR有效抑制NSCLC和顺铂耐药细胞中的EGFR/AKT信号传导并增强顺铂敏感性，表明其作为一种有前景的肺癌治疗策略的潜力。
