Wei Xiaoli, Li Ming, Ma Mingming, Jia Huina, Zhang Yu, Kang Wenyi, Wang Tianxiao, Shi Xiaoyan
Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan 475004, P.R. China.
Oncol Lett. 2017 Feb;13(2):791-799. doi: 10.3892/ol.2016.5522. Epub 2016 Dec 20.
Pyruvate kinase isoenzyme M2 (PKM2) has previously been identified as a tumor biomarker and as a potential target for cancer therapy. In this study, F§FJ-5, a characterized naphthoquinone modifier of mollugin, was synthesized in order to investigate its anticancer activity and the potential mechanisms. It was observed that FFJ-5 inhibited the cell growth of human lung adenocarcinoma cells A549 and human hepatoma cells HepG2 by MTT assays. FFJ-5 arrested cell cycle at the G2/M phase. Further analyses demonstrated that FFJ-5 attenuated the expression of PKM2 and reduced the production of adenosine triphosphate (ATP). Reduced expression and activity of epidermal growth factor receptor (EGFR) and Akt were observed in A549 and HepG2 cells exposed to FFJ-5. FFJ-5 exposure also resulted in cell apoptosis, in association with decreased intracellular pH level and mitochondrial membrane potential. In addition, FFJ-5 activated the caspase-3 cascade. In conclusion, FFJ-5 inhibited cancer cell growth via the blocking the EGFR-Akt-PKM2 pathway or through the synergistic action of EGFR, Akt and PKM2 proteins, alongside a decrease in ATP production. In addition, FFJ-5 induced cancer cell apoptosis by decreasing the intracellular pH level and the mitochondrial apoptosis pathway. The present results suggest a potential role of FFJ-5 on the therapy of human cancer.
丙酮酸激酶同工酶M2（PKM2）先前已被鉴定为一种肿瘤生物标志物以及癌症治疗的潜在靶点。在本研究中，合成了一种具有特征性的萘醌修饰的莫洛苷（F§FJ-5），以研究其抗癌活性及潜在机制。通过MTT试验观察到F§FJ-5抑制人肺腺癌细胞A549和人肝癌细胞HepG2的细胞生长。F§FJ-5使细胞周期停滞在G2/M期。进一步分析表明，F§FJ-5减弱了PKM2的表达并降低了三磷酸腺苷（ATP）的产生。在暴露于F§FJ-5的A549和HepG2细胞中观察到表皮生长因子受体（EGFR）和Akt的表达及活性降低。F§FJ-5处理还导致细胞凋亡，伴有细胞内pH值水平和线粒体膜电位降低。此外，F§FJ-5激活了caspase-3级联反应。总之，F§FJ-5通过阻断EGFR-Akt-PKM2途径或通过EGFR、Akt和PKM2蛋白的协同作用抑制癌细胞生长，同时ATP产生减少。此外，F§FJ-5通过降低细胞内pH值水平和线粒体凋亡途径诱导癌细胞凋亡。目前的结果表明F§FJ-5在人类癌症治疗中具有潜在作用。
