Irreversible epidermal growth factor receptor inhibitor Z25h exhibits pronounced inhibition on non-small cell lung adenocarcinoma cell line Hcc827
| Autor: | Wei Li, San-Qi Zhang, Yong-Xiao Cao, Hong-Ying Wang, Ping-Ping Yan, Shuai Tan, Xue Xiao, Jin Wang, Zhang Hao |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Lung Neoplasms Cell cycle checkpoint Cell Adenocarcinoma of Lung Cell Line Tumor medicine Humans Pharmacology (medical) Epidermal growth factor receptor Protein kinase B PI3K/AKT/mTOR pathway Pharmacology A549 cell biology Chemistry Cell Cycle Checkpoints ErbB Receptors Pyrimidines medicine.anatomical_structure Oncology A549 Cells Cell culture Apoptosis Cancer research biology.protein |
| Zdroj: | Anti-Cancer Drugs. 32:417-426 |
| ISSN: | 0959-4973 |
| DOI: | 10.1097/cad.0000000000001012 |
| Popis: | The epidermal growth factor receptor (EGFR) signaling is frequently activated in lung cancer. In our previous study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-tyrosine kinase inhibitors to overcome acquired EGFR-T790M resistance. In this study, we selected the most promising compound Z25h to further investigate its effects and the underlying mechanism against non-small cell lung adenocarcinoma cells in vitro. Four different non-small cell lung adenocarcinoma cell lines were selected to test the antiviability profile of Z25h, and Hcc827 was the most sensitive to the drug treatment. Z25h caused cell cycle arrest at G0-G1 phase, and triggered strong early apoptosis in Hcc827 cells at 0.1 μM and late apoptosis in A549, H1975 and H1299 cells at 10 μM by 48 h treatment. Z25h inhibited the activation of EGFR and its downstream PI3K/AKT/mTOR pathway in the four tested cell lines, leading to the inhibition of cellular biosynthetic and metabolic processes and the promotion of apoptotic process. However, the effect of Z25h on mitogen-activated protein kinase pathway varies from cell lines. In addition, Z25h sensitized H1975 cells to X-ray radiation, and it also enhanced the radiation effect on A549 cells, while no obvious effect of Z25h was observed on the cell viability inhibition of H1299 cells induced by radiation. Hereby, Z25h might be considered as a potential therapeutic drug candidate for non-small cell lung adenocarcinoma treatment. |
| Databáze: | OpenAIRE |
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