Quinalizarin, a specific CK2 inhibitor, can reduce icotinib resistance in human lung adenocarcinoma cell lines
Autor: | Qianwen Li, Rui Meng, Sheng Zhang, Li Liu, Ke Li, Yu Zhou, Fangzheng Zhou, Zhenyu Li, Gang Wu |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Lung Neoplasms proliferation Adenocarcinoma of Lung Anthraquinones Antineoplastic Agents quinalizarin 03 medical and health sciences T790M chemistry.chemical_compound 0302 clinical medicine icotinib Cell Line Tumor Crown Ethers Genetics Humans Epidermal growth factor receptor Protein kinase A Casein Kinase II Protein kinase B Protein Kinase Inhibitors Cell Proliferation protein kinase casein kinase II Quinalizarin biology Chemistry apoptosis General Medicine Articles Cell cycle respiratory tract diseases 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Icotinib Cancer research biology.protein Quinazolines Casein kinase 2 |
Zdroj: | International Journal of Molecular Medicine |
ISSN: | 1791-244X 1107-3756 |
Popis: | The abnormal activation of the downstream signaling pathways of epidermal growth factor receptor (EGFR) that are independent of EGFR, contribute to the acquisition of EGFR-tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). The serine/threonine protein kinase casein kinase II (CK2) phosphorylates and modulates several members of the EGFR downstream signaling pathways. Thus, the purpose of the current study was to investigate the effects of the addition of quinalizarin (a specific CK2 inhibitor) to icotinib (an EGFR-TKI) on the proliferation and apoptosis of four NSCLC cell lines and its underlying mechanisms. The human lung adenocarcinoma cell lines HCC827, A549, H1650 and H1975 were employed to represent the EGFR-TKI-sensitive EGFR (EGFR-sensitive) mutation, wild-type EGFR and the EGFR-TKI-resistant EGFR (EGFR-resistant) mutations. The cell viability was determined by the MTT assay. Cell apoptosis was detected by flow cytom-etry using the Annexin V-enhanced green fluorescent protein Apoptosis Detection kit. The level of proteins in the EGFR downstream pathway was observed using a western blot assay. The results showed that the cells with the EGFR-sensitive mutation (HCC827, EGFR E716-A750del) were more sensitive to icotinib compared with those possessing the EGFR wild-type (A549) and the EGFR-resistant mutations (H1650, EGFR E716-A750del and PTEN lost; H1975, EGFR L858R+T790M). Quinalizarin inhibited proliferation and promoted apoptosis in the cells with the EGFR wild-type and resistant mutations, and the addition of quinalizarin to icotinib partially restored their sensitivity to icotinib. Quinalizarin and/or icotinib increased the apoptotic rates in the EGFR-TKI resistant cells, and the combination of these reduced the level of protein downstream of EGFR, including phosphorylated (p-AKT) and p-(ERK). In conclusion, quinalizarin may partially sensitize cells to icotinib by inhibiting proliferation and promoting apoptosis mediated by AKT and ERK in EGFR-TKI resistant NSCLC cell lines. |
Databáze: | OpenAIRE |
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