Somboonvoravong Worawich, Petsri Korrakod, Racha Satapat, Sriratanasak Nicharat, Joyjamras Keerati, Sritularak Boonchoo, Chanvorachote Pithi
Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Graduate Program of Pharmaceutical Sciences and Technology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Anticancer Res. 2025 Jul;45(7):2833-2845. doi: 10.21873/anticanres.17652.
BACKGROUND/AIM: NSCLC severity is driven by dysregulation of the EGFR/PI3K/Akt pathway, promoting tumor growth and drug resistance. Hyperactive EGFR/PI3K/Akt signaling results in aggressive tumors and poor patient outcomes, worsened by resistance to EGFR inhibitors. Therefore, targeting this pathway may inhibit tumor growth and induce resistance. Artogomezianone, a compound derived from , has shown considerable anti-cancer efficacy, mainly by inducing apoptosis and decreasing the proliferation of several cancer types. In this study, artogomezianone was investigated regarding its inhibitory effects on the EGFR/PI3K/Akt pathway.
Cytotoxicity and primarily apoptotic induction effects were examined by the MTT assay and Hoechst 33342 and propidium iodide staining and confirmed by western blot analysis. In addition, western blot analysis and molecular docking were used to determine the protein levels and binding affinity of compound and significant proteins in EGFR/PI3K/Akt pathway.
Artogomezianone showed cytotoxicity and apoptotic induction effects against A549 (NSCLC) cells. It increased the cleavage of PARP and decreased procaspase-9 protein levels. In the EGFR/PI3K/Akt pathway, artogomezianone caused significant decrease in p-PI3K/PI3K and p-Akt/Akt protein levels. Moreover, molecular docking analysis showed that artogomezianone could bind EGFR ATP-binding site with greater affinity than erlotinib, the formal EGFR inhibitor.
For the first time, it was demonstrated that artogomezianone has an anti-cancer effect via direct interaction with EGFR proteins in the EGFR/PI3K/Akt pathway and causes the inhibitory effects of its downstream proteins (PI3K and Akt), resulting in an induction of NSCLC apoptosis.
背景/目的：非小细胞肺癌（NSCLC）的严重程度由表皮生长因子受体（EGFR）/磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（Akt）信号通路失调驱动，促进肿瘤生长和耐药。EGFR/PI3K/Akt信号过度激活导致侵袭性肿瘤和患者预后不良，而对EGFR抑制剂的耐药性会使其恶化。因此，靶向该信号通路可能抑制肿瘤生长并诱导耐药。源自[具体来源未给出]的化合物artogomezianone已显示出相当大的抗癌功效，主要通过诱导凋亡和减少几种癌症类型的增殖。在本研究中，对artogomezianone对EGFR/PI3K/Akt信号通路的抑制作用进行了研究。
通过MTT法、Hoechst 33342和碘化丙啶染色检测细胞毒性和主要的凋亡诱导作用，并通过蛋白质印迹分析进行确认。此外，使用蛋白质印迹分析和分子对接来确定化合物与EGFR/PI3K/Akt信号通路中重要蛋白质的蛋白水平和结合亲和力。
Artogomezianone对A549（NSCLC）细胞显示出细胞毒性和凋亡诱导作用。它增加了聚（ADP-核糖）聚合酶（PARP）的裂解，并降低了原半胱天冬酶-9蛋白水平。在EGFR/PI3K/Akt信号通路中，artogomezianone导致p-PI3K/PI3K和p-Akt/Akt蛋白水平显著降低。此外，分子对接分析表明，artogomezianone与EGFR ATP结合位点的结合亲和力高于正式的EGFR抑制剂厄洛替尼。
首次证明artogomezianone通过与EGFR/PI3K/Akt信号通路中的EGFR蛋白直接相互作用具有抗癌作用，并导致其下游蛋白（PI3K和Akt）的抑制作用，从而诱导NSCLC凋亡。
