Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University.
Department of Pharmacology, Shandong College of Traditional Chinese Medicine.
Biosci Trends. 2019;13(1):40-48. doi: 10.5582/bst.2019.01006.
The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of phosphoinositide 3-kinase (PI3K) and reported to inhibit tumor growth. However, its chiral structure and poor solubility prevent its further use. Compound 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) is an analogue of S14161 produced by structural optimization. A previous study indicated that BENC-511 acted on multiple myeloma and that it had a toxicity by inhibiting the PI3K/protein kinase B (Akt) pathway. However, the effects of BENC-511 on the proliferation and apoptosis of A549 human lung adenocarcinoma cells have not been reported. The current study investigated the effects of BENC-511 on the proliferation and apoptosis of A549 cells in vitro. Results indicated that the compound BENC-511 inhibited the viability of A549 cells in a concentration- and time- dependent manner. BENC-511 suppressed proliferation and colony formation via S phase arrest. BENC-511 decreased the expression of cyclin A, proliferating cell nuclear antigen (PCNA), B-cell lymphoma-2 (Bcl-2), phospho-mammalian target of rapamycin (p-mTOR), and phospho-Akt (p-Akt) and it increased the expression of p21WAF1CIP1(p21), Caspase-3 and Caspase-9. In conclusion, BENC-511 inhibited the proliferation of A549 human lung adenocarcinoma cells via S phase arrest as a result of up-regulation of p21 and reduction of Cyclin A/cyclin-dependent kinase 2 (CDK2)/PCNA complex and it induced apoptosis by reducing the mitochondrial membrane potential via the Akt/Bcl-2/Caspase-9 mitochondrial pathway of apoptosis.
小分子化合物 8-乙氧基-2-(4-氟苯基)-3-硝基-2H-色烯（S14161）最近被鉴定为磷酸肌醇 3-激酶（PI3K）的抑制剂，并被报道能抑制肿瘤生长。然而，其手性结构和较差的溶解度阻碍了其进一步的应用。化合物 6-溴-8-乙氧基-3-硝基-2H-色烯（BENC-511）是 S14161 的结构优化类似物。先前的研究表明，BENC-511 作用于多发性骨髓瘤，通过抑制 PI3K/蛋白激酶 B（Akt）通路发挥毒性作用。然而，BENC-511 对 A549 人肺腺癌细胞增殖和凋亡的影响尚未报道。本研究探讨了 BENC-511 对 A549 细胞体外增殖和凋亡的影响。结果表明，该化合物 BENC-511 呈浓度和时间依赖性地抑制 A549 细胞活力。BENC-511 通过 S 期阻滞抑制增殖和集落形成。BENC-511 降低了细胞周期蛋白 A、增殖细胞核抗原（PCNA）、B 细胞淋巴瘤-2（Bcl-2）、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）和磷酸化 Akt（p-Akt）的表达，增加了 p21WAF1CIP1（p21）、Caspase-3 和 Caspase-9 的表达。综上所述，BENC-511 通过上调 p21 和降低细胞周期蛋白 A/细胞周期蛋白依赖性激酶 2（CDK2）/PCNA 复合物，通过抑制 Akt/Bcl-2/Caspase-9 线粒体凋亡途径降低线粒体膜电位，抑制 A549 人肺腺癌细胞增殖，并诱导凋亡。
