Lee Na Yeong, Joo Sang Hoon, Nam A-Young, Lee Seung-On, Yoon Goo, Cho Seung-Sik, Choi Yung Hyun, Park Jin Woo, Shim Jung-Hyun
Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea.
College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea.
EXCLI J. 2024 Oct 21;23:1287-1302. doi: 10.17179/excli2024-7359. eCollection 2024.
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Its treatment is complicated due to the development of resistance to conventional chemotherapy and targeted therapy. Deoxybouvardin and related cyclic hexapeptides reportedly exhibit antitumor activities, but their mechanisms of action remain unclear. This study aimed to investigate the anticancer mechanisms of deoxybouvardin glucoside (DBG), a glucosidic form of deoxybouvardin from species, in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. The effects of DBG treatment on cell proliferation were evaluated using a viability assay. The inhibitory effects of DBG treatment on the activities and phosphorylation of the protein kinases epidermal growth factor receptor (EGFR), MET, and AKTs were assessed using kinase assay and western blot, respectively. DBG treatment inhibited the growth of HCC827 cells in a concentration- and time-dependent manner. Results of kinase assay and western blotting showed that DBG treatment significantly inhibited the activities and phosphorylation of the protein kinases EGFR, MET, and AKT. Prediction using molecular docking showed that DBG is located in the ATP-binding pockets of these kinases, supporting the kinase inhibition by DBG treatment. Moreover, DBG treatment induced reactive oxygen species (ROS) generation and cell cycle arrest in the cells. The induction of apoptosis by DBG through caspase activation was confirmed by Z-VAD-FMK treatment. In summary, DBG treatment inhibited the growth of GEF-sensitive and -resistant NSCLC cells by targeting EGFR, MET, and AKTs. Moreover, it induced apoptosis by inducing ROS generation and caspase activation. These results indicate that DBG is a potential therapeutic agent for the treatment of GEF-resistant NSCLC. See also the graphical abstract(Fig. 1).
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因。由于对传统化疗和靶向治疗产生耐药性，其治疗较为复杂。据报道，脱氧布瓦西丁及相关环六肽具有抗肿瘤活性，但其作用机制尚不清楚。本研究旨在探讨脱氧布瓦西丁糖苷（DBG），一种从[物种名称]中提取的脱氧布瓦西丁的糖苷形式，对吉非替尼（GEF）敏感和耐药的NSCLC HCC827细胞的抗癌机制。使用活力测定法评估DBG处理对细胞增殖的影响。分别使用激酶测定法和蛋白质印迹法评估DBG处理对蛋白激酶表皮生长因子受体（EGFR）、MET和AKT的活性及磷酸化的抑制作用。DBG处理以浓度和时间依赖性方式抑制HCC827细胞的生长。激酶测定和蛋白质印迹结果表明，DBG处理显著抑制蛋白激酶EGFR、MET和AKT的活性及磷酸化。分子对接预测表明，DBG位于这些激酶的ATP结合口袋中，支持DBG处理对激酶的抑制作用。此外，DBG处理诱导细胞内活性氧（ROS）生成和细胞周期停滞。Z-VAD-FMK处理证实DBG通过半胱天冬酶激活诱导细胞凋亡。总之，DBG处理通过靶向EGFR、MET和AKT抑制GEF敏感和耐药NSCLC细胞的生长。此外，它通过诱导ROS生成和半胱天冬酶激活诱导细胞凋亡。这些结果表明，DBG是治疗GEF耐药NSCLC的潜在治疗药物。另见图1的图形摘要。
