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脱氧博伐他汀通过靶向 EGFR、MET 和 AKT 信号通路抑制非小细胞肺癌细胞。

Deoxybouvardin targets EGFR, MET, and AKT signaling to suppress non-small cell lung cancer cells.

机构信息

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.

出版信息

Sci Rep. 2024 Sep 6;14(1):20820. doi: 10.1038/s41598-024-70823-7.

DOI:10.1038/s41598-024-70823-7
PMID:39242647
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11379681/
Abstract

Non-small cell lung cancer (NSCLC) remains a significant challenge, as it is one of the leading causes of cancer-related deaths, and the development of resistance to anticancer therapy makes it difficult to treat. In this study, we investigated the anticancer mechanism of deoxybouvardin (DB), a cyclic hexapeptide, in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. DB inhibited the viability and growth of HCC827 cells in a concentration- and time-dependent manner. In vitro kinase assay showed DB inhibited epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition (MET), and AKT, and their phosphorylation was suppressed in HCC827 cells treated with DB. A molecular docking model suggested that DB interacts with these kinases in the ATP-binding pockets. DB induces ROS generation and cell cycle arrest. DB treatment of HCC827 cells leads to mitochondrial membrane depolarization. The induction of apoptosis through caspase activation was confirmed by Z-VAD-FMK treatment. Taken together, DB inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on DB can improve the treatment of chemotherapy-resistant NSCLC through the development of effective DB-based anticancer agents.

摘要

非小细胞肺癌 (NSCLC) 仍然是一个重大挑战，因为它是癌症相关死亡的主要原因之一，并且对抗癌治疗的耐药性使得治疗变得困难。在这项研究中，我们研究了环状六肽脱氧博伐丁 (DB) 在吉非替尼 (GEF) 敏感和耐药 NSCLC HCC827 细胞中的抗癌机制。DB 以浓度和时间依赖的方式抑制 HCC827 细胞的活力和生长。体外激酶测定表明，DB 抑制表皮生长因子受体 (EGFR)、间质-上皮转化 (MET) 和 AKT，并且在 DB 处理的 HCC827 细胞中它们的磷酸化受到抑制。分子对接模型表明 DB 与这些激酶在 ATP 结合口袋中相互作用。DB 诱导 ROS 生成和细胞周期停滞。DB 处理 HCC827 细胞导致线粒体膜去极化。通过 caspase 激活诱导的细胞凋亡通过 Z-VAD-FMK 处理得到证实。总之，DB 通过靶向 EGFR、MET 和 AKT 并诱导 ROS 生成和 caspase 激活来抑制 GEF 敏感和 GEF 耐药 NSCLC 细胞的生长。对 DB 的进一步研究可以通过开发有效的基于 DB 的抗癌药物来改善对化疗耐药 NSCLC 的治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/833f434b37c2/41598_2024_70823_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/e752f8ba3067/41598_2024_70823_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/b5414fdb420d/41598_2024_70823_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/e1a530458c4c/41598_2024_70823_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/4a5511586062/41598_2024_70823_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/2239fe296d72/41598_2024_70823_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/621062cbd3ed/41598_2024_70823_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/e9fff1156889/41598_2024_70823_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/262b8086d824/41598_2024_70823_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/833f434b37c2/41598_2024_70823_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/e752f8ba3067/41598_2024_70823_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/b5414fdb420d/41598_2024_70823_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/e1a530458c4c/41598_2024_70823_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/4a5511586062/41598_2024_70823_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/2239fe296d72/41598_2024_70823_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/621062cbd3ed/41598_2024_70823_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/e9fff1156889/41598_2024_70823_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/262b8086d824/41598_2024_70823_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e832/11379681/833f434b37c2/41598_2024_70823_Fig9_HTML.jpg

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